Cancer reactive t cell receptors

Abstract

The present disclosure relates in some aspects to modified lymphocytes comprising engineered cancer reactive y8 T Cell Receptors.

Description

Attorney Docket No.: 304952000240 CANCER REACTIVE T CELL RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 558,527, filed on February 27, 2024, entitled “CANCER REACTIVE T CELL RECEPTORS”, which is herein incorporated by reference in its entirety for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (304952000240seqlist.xml; Size: 843,562 bytes; and Date of Creation: February 19, 2025) is herein incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present disclosure relates in some aspects to modified lymphocytes comprising cancer reactive γδ T Cell Receptors. BACKGROUND

[0004] Major histocompatibility complex (MHC)-independent, T cell–mediated targeting of cancer cells could improve current immunotherapies and could allow immune destruction of malignancies in all individuals. Unconventional T cells do not recognize classical peptide– major histocompatibility complex (pMHC) ligands and can express αβ or γδ TCRs. For instance, a significant portion of human Vγ9Vδ2 T cells recognizes phosphorylated isoprenoid intermediates of lipid biosynthesis in the context of butyrophilin 3A11. However, the ligands recognized by many unconventional T cells remain unknown. Improved cellular therapies comprising gamma-delta T cell Receptors (TCRs) with reactivity to cancer cells are therefore needed. Provided herein are modified lymphocytes and compositions that address such and other needs. SUMMARY

[0005] In some aspects, provided herein is a modified lymphocyte comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR further comprises, a CDR1, a and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:601, and a CDR1, a CDR2, andAttorney Docket No.: 304952000240 a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:602; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:603, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:604; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:605, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:606; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:607, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:608; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:609, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:610; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:611, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:612; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:613, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:614; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:615, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:616; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:617, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:618; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:619, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:620; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:621, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:622; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:623, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:624; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:625, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the acid sequence set forth in SEQ ID NO:626; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:627, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:628; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:629, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:630; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:631, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:632; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:633, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:634; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:635, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:636; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:637, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:638; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:639, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:640; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:641, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:642; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:643, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:644; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:645, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:646; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:647, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:648; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:649, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:650; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:651, and a a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:652; a CDR1, a CDR2,Attorney Docket No.: 304952000240 and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:653, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:654; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:655, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:656; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:657, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:658; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:659, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:660; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:661, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:662; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:663, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:664; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:665, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:666; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:667, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:668; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:669, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:670; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:671, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:672; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:673, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:674; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:675, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:676; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising amino acid sequence set forth in SEQ ID NO:677, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:678; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:679, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:680; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:681, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:682; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:683, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:684; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:685, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:686; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:687, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:688; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:689, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:690; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:691, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:692; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:693, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:694; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:695, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:696; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:697, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:698; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:699, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:700; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:701, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:702; a a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:703, and a CDR1, a CDR2, andAttorney Docket No.: 304952000240 a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:704; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:705, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:706; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:707, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:708; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:709, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:710; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:711, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:712; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:713, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:714; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:715, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:716; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:717, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:718; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:719, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:720; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:721, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:722; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:723, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:724; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:725, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:726; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:727, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the acid sequence set forth in SEQ ID NO:728; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:729, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:730; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:731, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:732; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:733, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:734; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:735, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:736; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:737, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:738; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:739, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:740; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:741, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:742; or a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:743, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:744; and wherein the modified lymphocyte is reactive to a cancer cell.

[0006] In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:301, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:302, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:303; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6, and wherein the TCR- δ extracellular antigen binding domain a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:304, a CDR2 comprising the amino acid sequence set forthAttorney Docket No.: 304952000240 in SEQ ID NO:305, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:306; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:8, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:307, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:308, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:309; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:310, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:311, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:312; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:13, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:15, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:313, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:314, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:315; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:16, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:18, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:316, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:317, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:318; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:21, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:319, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:320, and a CDR3 the amino acid sequence set forth in SEQ ID NO:321; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprisingAttorney Docket No.: 304952000240 the amino acid sequence set forth in SEQ ID NO:22, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:322, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:323, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:324; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:325, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:326, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:327; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:30, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:328, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:329, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:330; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:33, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:331, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:332, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:333; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:36, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:334, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:336; the TCR-γ extracellular antigen binding domain comprises a CDR1 the amino acid sequence set forth in SEQ ID NO:37, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:38, and aAttorney Docket No.: 304952000240 CDR3 comprising the amino acid sequence set forth in SEQ ID NO:39, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:337, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:338, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:339; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:42, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:340, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:341, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:342; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:43, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:45, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:343, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:344, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:345; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:346, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:347, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:348; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:349, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:350, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:351; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, and a comprising the amino acid sequence set forth in SEQ ID NO:54, and wherein the TCR-δ extracellular antigen binding domainAttorney Docket No.: 304952000240 comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:352, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:353, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:354; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:56, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:57, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:355, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:356, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:357; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:58, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:59, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:60, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:358, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:359, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:360; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:61, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:62, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:63, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:361, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:362, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:363; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:66, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:364, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:365, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:366; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:69, and wherein the TCR-δ extracellular antigen binding domain a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:367, a CDR2 comprising the amino acid sequence set forthAttorney Docket No.: 304952000240 in SEQ ID NO:368, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:369; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:70, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:71, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:72, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:370, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:371, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:372; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:73, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:74, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:75, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:373, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:374, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:375; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:76, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:77, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:78, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:376, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:377, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:378; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:79, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:80, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:81, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:379, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:380, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:381; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:82, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:84, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:382, a CDR2 comprising the amino acid sequence set forth SEQ ID NO:383, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:384; the TCR-γ extracellular antigenAttorney Docket No.: 304952000240 binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:86, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:385, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:386, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:387; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:88, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:89, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:90, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:388, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:389, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:390; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:91, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:92, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:93, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:391, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:392, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:393; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:94, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:96, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:394, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:395, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:396; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:99, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:397, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:398, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:399; the TCR-γ extracellular antigen domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:100, a CDR2 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:101, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:102, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:400, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:401, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:402; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:103, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:104, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:105, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:403, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:404, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:405; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:106, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:108, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:406, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:407, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:408; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:409, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:410, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:411; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:114, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:412, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:413, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:414; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:115, a CDR2 comprising the amino acid set forth in SEQ ID NO:116, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:117, and wherein theAttorney Docket No.: 304952000240 TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:415, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:416, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:417; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:118, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:119, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:120, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:418, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:419, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:420; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:122, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:421, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:422, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:423; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:125, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:126, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:424, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:425, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:426; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:127, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:128, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:129, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:427, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:428, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:429; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:130, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:131, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:132, and wherein the δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:430, a CDR2Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:431, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:432; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:133, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:134, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:135, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:433, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:434, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:435; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:136, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:137, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:138, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:436, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:437, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:438; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:139, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:140, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:141, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:439, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:440, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:441; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:142, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:143, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:144, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:442, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:443, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:444; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:145, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:146, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:147, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:445, a the amino acid sequence set forth in SEQ ID NO:446, and a CDR3 comprising the amino acid sequence set forth in SEQ IDAttorney Docket No.: 304952000240 NO:447; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:148, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:149, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:150, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:448, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:449, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:450; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:151, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:152, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:153, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:451, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:452, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:453; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:454, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:455, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:456; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:457, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:458, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:459; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:460, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:461, and a CDR3 comprising the amino acid sequence set forth in SEQ ID the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ IDAttorney Docket No.: 304952000240 NO:163, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:164, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:165, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:463, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:464, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:465; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:166, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:167, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:168, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:466, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:467, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:468; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:169, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:170, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:171, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:469, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:470, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:471; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:472, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:473, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:474; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:175, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:176, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:177, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:475, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:476, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:477; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:179, and a CDR3 comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:180, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:478, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:479, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:480; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:183, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:481, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:482, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:483; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:184, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:185, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:186, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:484, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:485, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:486; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:187, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:188, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:189, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:487, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:488, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:489; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:190, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:191, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:192, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:490, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:491, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:492; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:193, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:194, and a CDR3 comprising the amino acid sequence in SEQ ID NO:195, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:493, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:494, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:495; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:196, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:197, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:198, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:496, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:497, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:498; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:199, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:200, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:201, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:499, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:500, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:501; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:202, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:203, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:204, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:502, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:503, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:504; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:205, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:206, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:207, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:505, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:506, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:507; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:208, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:210, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino set forth in SEQ ID NO:508, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:509, and a CDR3 comprisingAttorney Docket No.: 304952000240 the amino acid sequence set forth in SEQ ID NO:510; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:211, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:212, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:213, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:511, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:512, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:513; or the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:214, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:215, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:216, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:514, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:515, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:516.

[0007] In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:601, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:602; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:603, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:604; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:605, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:606; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:607, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:608; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:609, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:610; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:611, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:612; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:613, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:614; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:615, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:616; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:617, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:618; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:619, and the TCR-δ chain comprises the acid sequence set forth in SEQ ID NO:620; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:621,Attorney Docket No.: 304952000240 and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:622; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:623, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:624; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:625, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:626; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:627, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:628; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:629, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:630; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:631, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:632; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:633, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:634; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:635, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:636; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:637, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:638; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:639, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:640; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:641, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:642; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:643, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:644; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:645, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:646; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:647, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:648; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:649, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:650; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:651, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:652; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:653, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:654; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:655, and the TCR-δ chain comprises the amino acid sequence set in SEQ ID NO:656; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:657, and the TCR-δ chainAttorney Docket No.: 304952000240 comprises the amino acid sequence set forth in SEQ ID NO:658; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:659, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:660; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:661, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:662; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:663, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:664; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:665, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:666; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:667, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:668; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:669, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:670; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:671, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:672; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:673, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:674; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:675, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:676; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:677, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:678; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:679, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:680; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:681, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:682; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:683, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:684; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:685, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:686; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:687, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:688; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:689, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:690; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:691, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:693, and the TCR-δ chain comprises the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:694; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:695, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:696; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:697, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:698; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:699, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:700; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:701, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:702; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:703, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:704; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:705, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:706; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:707, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:708; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:709, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:710; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:711, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:712; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:713, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:714; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:715, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:716; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:717, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:718; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:719, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:720; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:721, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:722; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:723, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:724; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:725, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:726; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:727, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:728; the TCR-γ chain the amino acid sequence set forth in SEQ ID NO:729, and the TCR-δ chain comprises the amino acid sequence set forth in SEQAttorney Docket No.: 304952000240 ID NO:730; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:731, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:732; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:733, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:734; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:735, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:736; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:737, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:738; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:739, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:740; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:741, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:742; or the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:743, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:744.

[0008] In some aspects, provided herein is a modified lymphocyte comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR further comprises: a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 601, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 602; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 617 , and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 618; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 657, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 658; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 699, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 700; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 703, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 704; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid set forth in SEQ ID NO: 705, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth inAttorney Docket No.: 304952000240 SEQ ID NO: 706; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:707, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 708; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:715, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:716; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:721, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 722; or a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:745, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:746.

[0009] In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:301, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:302, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:303; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:325, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:326, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:327; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:86, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:385, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:386, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:387; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:148, a CDR2 comprising the amino acid set forth in SEQ ID NO:149, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:150, and wherein theAttorney Docket No.: 304952000240 TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:448, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:449, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:450; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:454, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:455, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:456; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:457, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:458, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:459; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:460, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:461, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:462; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:472, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:473, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:474; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:183, and wherein the δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:481, a CDR2Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:482, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:482; or the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:217, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:218, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:219, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:517, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:518, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:519.

[0010] In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:601, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:602; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:617, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:618; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:657, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:658; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:699, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:700; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:703, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:704; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:705, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:706; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:707, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:708; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:715, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:716; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:721, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:722; or the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:745, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:746.

[0011] In some embodiments, the TCR comprises a Vδ1+ chain, a Vδ2+chain, or a Vδ3+ chain. In some embodiments, the TCR is a Vγ9Vδ2 gamma-delta TCR. In some embodiments, the TCR comprise a Vγ9 chain. In some embodiments, the TCR is a non- Vγ9Vδ2 gamma-delta TCR.Attorney Docket No.: 304952000240

[0012] In some embodiments, the transmembrane domain comprises an amino acid sequence set forth in SEQ ID NOs:551-552. In some embodiments, the TCR-γ chain comprises a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:551. In some embodiments, the TCR-δ chain comprises a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:552.

[0013] In some embodiments, wherein the intracellular domain comprises an amino acid sequence set forth in SEQ ID NOs:561-562.In some embodiments, the TCR-γ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:561. In some embodiments, the TCR-δ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:562.

[0014] In some embodiments, the modified lymphocyte is a CD3+ T cell. In some embodiments, the modified lymphocyte is a CD4+ T cell or a CD8+ T cell. In some embodiments, the modified lymphocyte is a gamma-delta T cell. In some embodiments, the modified lymphocyte is a primary human lymphocyte. In some embodiments, the modified lymphocyte is an autologous lymphocyte.

[0015] In some embodiments, the modified lymphocyte is reactive toward a single cancer cell type. In some embodiments, the modified lymphocyte is reactive toward more than one cancer cell type. In some embodiments, the modified lymphocyte is reactive toward two, three, four, or five cancer cell types.

[0016] In some embodiments, the modified lymphocyte comprises enhanced cytotoxicity towards a cancer cell type compared to the cytotoxicity of an unmodified lymphocyte to the same cancer cell type.

[0017] In some embodiments, the modified lymphocyte comprises an immunosuppressive resistance gene that enhances cytotoxicity towards a cancer cell type compared to the cytotoxicity of a lymphocyte that does not comprise the immunosuppressive resistance gene to the same cancer cell type. In some embodiments, the immunosuppressive resistance gene is LTBR.

[0018] In some embodiments, the modified lymphocyte further comprises a co-stimulatory protein or a functional portion thereof that enhances cytotoxicity towards a cancer cell type compared to the cytotoxicity of a lymphocyte that does not comprise the co-stimulatory protein or functional portion thereof to the same cancer cell type. In some embodiments, the co-stimulatory protein or functional portion thereof is CD80 or 4-1BBL.

[0019] In some embodiments, the cancer cell is selected from the group consisting of lung, breast, pancreatic, melanoma, colorectal, and ovarian cancer.Attorney Docket No.: 304952000240

[0020] In some embodiments, wherein the exogenous nucleic acid comprises an expression cassette comprising a promoter that is operably linked to the nucleic acid encoding the TCR. In some embodiments, the promoter is selected from the group consisting of cytomegalovirus (CMV) immediate-early enhancer, chicken beta-actin (CAG), human beta-actin, elongation factor 1α (EF1α), SV40, ubiquitin C (UbC), tetracycline response element (TRE), and PGK. In some embodiments, the promoter is a short EF-1α promoter. In some embodiments, the promoter is a ubiquitous promoter. In some embodiments, the promoter drives constitutive expression of the TCR. In some embodiments, the promoter is an inducible promoter. In some embodiments, the expression cassette further comprises a puromycin or blasticidin resistance gene.

[0021] In some embodiments, the expression cassette further comprises polynucleotides encoding an intracellular enzyme, an immunosuppressive resistance gene, a fluorescent protein, and / or a surface expressed safety switch protein. In some embodiments, the immunosuppressive resistance gene is LTBR. In some embodiments, the surface expressed safety switch protein comprises full length CD20, HER2, EGFR, and / or NGFR, or a functional fragment thereof.

[0022] In some embodiments, the expression cassette is integrated into the genome of the modified lymphocyte. In some embodiments, the expression cassette is integrated into a native TCR genomic locus of the modified lymphocyte. In some embodiments, the expression cassette is integrated into a safe harbor locus of the modified lymphocyte. In some embodiments, the expression cassette is randomly integrated into the genome of the modified lymphocyte.

[0023] In some embodiments, the nucleic acid encoding the TCR comprises a codon- optimized nucleic acid sequence set forth in SEQ ID NOs:801-946.

[0024] In other aspects, provided herein is a vector encoding an engineered TCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 4, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 4.

[0025] In some embodiments, the vector is a viral vector. In some embodiments, the vector is a lentivirus, an adenovirus, a retrovirus, or a baculovirus.

[0026] In some embodiments, the vector is an episomal or non-integrating vector. In some embodiments, the episomal vector is a Simian virus 40 (SV40), Adenovirus, or Adeno- associated vector.Attorney Docket No.: 304952000240

[0027] In some embodiments, the vector is a non-viral vector. In some embodiments, the non-viral vector is a plasmid. In some embodiments, the non-viral vector is delivered to a lymphocyte by electroporation or cell squeezing. In some embodiments, the non-viral vector is encapsulated in nanoparticles or liposomes.

[0028] In other aspects, provided herein is a method of killing cancer cells in an individual comprising providing to the individual a population of the modified lymphocyte described herein. In some embodiments, the cancer cells are selected from the group consisting of ovarian cancer cells, breast cancer cells, lung cancer cells, pancreatic cancer cells, colorectal cancer cells, and melanoma cancer cells.

[0029] In other aspects, provided herein is a method of treating cancer in an individual comprising providing to the individual a population of the modified lymphocyte described herein. In some embodiments, the cancer is a solid cancer. In some embodiments, the solid cancer is an epithelial cancer or a melanoma. In some embodiments, the epithelial cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer.

[0030] In other aspects, provided herein is a composition comprising the modified lymphocyte described herein.

[0031] In other aspects, provided herein is a method of identifying a γδ TCR that is reactive to one or more cancer types, the method comprising: a) isolating and expanding γδ T cells from one or more individuals diagnosed with cancer, each γδ T cell comprising a γδ TCR; b) culturing the γδ T cells expanded in step a) with multiple distinct cancer cell lines each comprising a cancer type, in separate wells, wherein each well contains a different cancer cell line and DNA-barcoded antibodies that bind to antigens expressed on the surface of the γδ T cells, wherein each DNA-barcode is associated with a particular cancer cell line used in the respective well; c) pooling the γδ T cells from each well of step b); d) identifying cancer reactive T cells from the pooled γδ T cells of step c); e) performing single cell sequencing on the cancer reactive γδ T cells from step d) to determine the sequence of the γδ TCR and to determine the sequence of the DNA barcode(s); and f) identifying the one or more cancer types that the γδ TCR is reactive to based upon detection of the barcode that is associated with the particular cancer cell line.

[0032] In some embodiments, the isolating and expanding the γδ T cells comprises a) expanding the γδ T cells in an oligoclonal format; and b) selecting clonal populations of the γδ T cells that recognize cancer cells via assay.Attorney Docket No.: 304952000240

[0033] In some embodiments, the γδ T cells are isolated from individuals diagnosed with cancers selected the group consisting of breast cancer and renal cell carcinoma. In some embodiments, the γδ T cells are isolated from peripheral blood mononuclear cells (PBMCs) obtained from enriched leukapheresis products. In some embodiments, the γδ T cells are isolated using a human Anti-TCRγ / δ MicroBead Kit or an EasySep Human Gamma / Delta T Cell Isolation Kit.

[0034] In some embodiments, the isolated T cells are cultured in T-cell media supplemented with recombinant human IL-2 and IL-15. In some embodiments, the isolated T cells are further activated by exposure to CD3 and CD28 agonists.

[0035] In some embodiments, the cancer cell lines are derived from solid tumors. In some embodiments, the cancer cells are selected from the group consisting of Capan-2, BxPC-3, A549, SK-OV-3, OVCAR-3, HT-29, HCT116, NCI-H1975, BT-549, MDA-MB-231, and HEK293FT. In some embodiments, the cancer cell lines are treated with zoledronic acid before culturing with the isolated γδ T cells. In some embodiments, the cancer cell lines are further labeled with IFNγ / TNFα capture agents.

[0036] In some embodiments, sorting the T cells based on cancer reactivity further comprises sorting the cells via flow-cytometry and gating the cells based on the expression of functional markers of T cell activation. In some embodiments, the functional markers of T cell activation are selected from the group consisting of TNFα, CD69, CD107a, and CD137.

[0037] In other aspects, provided herein is a gamma-delta TCR comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the gamma-delta TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 4, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 4.

[0038] In other aspects, provided herein is a method of treating cancer in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. wherein the modified lymphocyte is cancer reactive, the cancer is a solid cancer.Attorney Docket No.: 304952000240

[0039] In other aspects, provided herein is a method of killing cancer cells in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. wherein the modified lymphocyte is cancer reactive, wherein the cancer cells are derived from a solid cancer.

[0040] In some embodiments, the solid cancer is an epithelial cancer or a melanoma. In some embodiments, the epithelial cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer. In some embodiments, the solid cancer is an epithelial cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is selected from the group consisting of TCR_09, TCR_29, TCR_50, TCR_52, TCR_61, and TCR_73. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_52, TCR_53, TCR_54, TCR_61, and TCR_73. In some embodiments, the epithelial cancer is pancreatic cancer and the engineered TCR is TCR_09. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is selected from the group consisting of TCR_09, TCR_29, TCR_50, TCR_52, TCR_61, and TCR_73. In some embodiments, the solid cancer is a melanoma and the engineered TCR is selected from the group consisting of TCR_29, TCR_50, TCR_52, and TCR_73. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The drawings illustrate certain features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

[0042] FIGs. 1A-1B show the isolation and expansion of γδ T cells. FIG. 1A shows γδ T cell recovery, calculated by dividing the number of cells isolated by the number of cells expected based on the γδ T cell frequency in the sample. Isolation method #1 depicts a negativeAttorney Docket No.: 304952000240 selection approach comprising antibody labelling and magnetic removal of PBMC subsets other than gamma delta T cells. Isolation method #2 depicts a positive selection approach comprising antibody labelling and magnetic selection of cells expressing gamma-delta TCRs. FIG. 1B γδ T cell expansion after 12 days in culture with different IL-2 concentrations and CD3 / CD28 stimulation. Expansion method #1 comprises culturing the γδ T cells in T cell media supplemented with 50 IU / mL IL-2 only. Expansion method #2 comprises culturing the γδ T cells in T cell media supplemented with 50 IU / mL IL-2 + CD3 / CD28 antibodies. Expansion method #3 comprises culturing the γδ T cells in T cell media supplemented with 100 IU / mL IL-2 only. Expansion method #4 comprises culturing the γδ T cells in T cell media supplemented with 100 IU / mL IL-2 + CD3 / CD28 antibodies.

[0043] FIG. 2 shows selection of functional cancer-reactive γδ T cells. Isolated and expanded γδ T cells were cultured alone or co-cultured with cancer cells for 4-6 h, followed by the measurement of expression levels of selected activation markers by flow cytometry: CD69 and TNFα, CD137 and CD69, and CD107a and TNFα. Expression levels are expressed on a logarithmic scale. For TNFα detection, TAPI-0 was included for the duration of the assay. Zol indicates a 24 h pre-treatment of cancer cells with zoledronic acid to boost accumulation of phosphorylated isoprenoid intermediates of lipid biosynthesis.

[0044] FIGs. 3A-3B shows cytotoxicity of γδ T cells against cancer cells. γδ T cells from two donors, Donor 1 (FIG. 3A) and Donor 2 (FIG. 3B) were co-incubated with cancer cells and sorted based on activation markers (“Selected”). Following the selection, T cells were co- incubated again with a non-small cell lung cancer (NSCLC) line A549 and a triple negative breast cancer (TNBC) line MDA-MB-231. Both cancer cells lines were engineered to express nuclear GFP. After 72h of co-incubation, cytotoxicity was quantified as described in the Methods section.

[0045] FIG. 4 shows a schematic depiction of the use of DNA-barcoded antibodies to identify broadly cancer-reactive T cells.

[0046] FIG. 5 shows the identification of cancer-reactive T cells using ELISpot. Step 1: wells containing γδ T cells with cancer reactivity were selected by performing an IFNγ ELISpot on a portion of each well, using cancer cells to stimulate γδ T cells. The cancer- reactive γδ T cells then secrete IFNγ which was captured locally on the plate, resulting in a spot, enabling enumeration of cancer-reactive T cells in each well. Step 2: pre-selected wells with cancer-reactivity were pooled together and co-incubated with cancer cells in theAttorney Docket No.: 304952000240 presence of IFNγ / TNFα capture reagents, enabling further selection of T cells with cancer reactivity.

[0047] FIGs. 6A-6B show that TCR identification single cell multiomics assay enables robust assignment of pooled T cells to the corresponding cancer cell co-incubation condition. FIG. 6A shows dimensionality reduction on the signal from DNA-barcoded antibodies used to label each condition. UMAP - Uniform Manifold Approximation and Projection for Dimension Reduction. FIG. 6B show a low frequency of doublets (cells with a specific signal from multiple DNA-barcoded labelling antibodies), indicating lack of cross-contamination of DNA-barcoded antibodies between conditions and therefore robust assignment of reactive T cells to each condition.

[0048] FIG. 7 shows that the TCR identification single cell multiomics assay enables robust detection of TCR clonotypes with specific cancer reactivity. Each dot represents a unique γδ TCR. Fold enrichment in cancer reactivity was calculated by dividing the relative frequency of a given TCR pair within the sorted cancer-reactive population by its frequency in the control unsorted population. Cancer specificity is shown in pie charts for the top 4 TCRs based on the significance of enrichment.

[0049] FIGs. 8A-8B show the cancer specificity of the most enriched TCRs. Top significantly enriched TCRs based on the bulk enrichment as illustrated in FIG. 4 (FIG. 8A) or the oligoclonal enrichment as illustrated in FIG. 5 (FIG. 8B), are shown. TCR reactivity denotes the relative frequency of T cells responding to a given cancer indication as compared to all the cancer-reactive T cells bearing the same TCR.

[0050] FIG. 9 shows direct cytotoxicity of polyclonal CD3+ T cells engineered to express a selected cancer-reactive γδ TCR. T cells were lentivirally transduced with TCR_09 (Table 4, FIG. 8A) and their endogenous TCR was removed by nucleofection with Cas9 ribonucleoprotein complexed with a single guide RNA targeting TRBC1 and TRBC2 loci. Following expansion, engineered T cells were co-cultured with GFP-expressing cancer cell lines (lung: A549, breast: MDA-MB-231, pancreatic: Capan-2, colorectal: HCT-116, ovarian: SKOV3) for up to 90 h at effector:target ratio of 1:1 (MDA-MB-231, SKOV3, HCT-116) or 2:1 (Capan2, A549). Killing was calculated by comparing the relative count of GFP+ cells between wells containing both cancer cells and engineered T cells to the relative count of GFP+ cells in the wells containing cancer cells alone. n = 3, error bars indicate SEM.

[0051] FIGs. 10A-10B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_01 against A549 lung (FIG. 10A) and SK-OV-3 ovarian cancerAttorney Docket No.: 304952000240 (FIG. 10B) cell lines at the effector:target ratio of 4:1. Irrelevant TCR recognized phosphorylated metabolites sensed in the context of butyrophilin 3A1 molecule. n = 3, bars represent S.E.M.

[0052] FIGs. 11A-11C show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_61 against A549 lung cancer (FIG. 11A), SK-OV-3 ovarian cancer (FIG. 11B) and MDA-MB-231 breast cancer (FIG. 11C) cell lines at the effector:target ratio of 4:1. Irrelevant TCR recognized phosphorylated metabolites sensed in the context of butyrophilin 3A1 molecule. n = 3, bars represent S.E.M.

[0053] FIGs. 12A-12B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_58 against the SK-OV-3 (FIG. 12A) and OV90 (FIG. 12B) ovarian cancer lines at the effector:target ratio of 4:1. Irrelevant gene is truncated EGFR. n = 3, bars represent S.E.M.

[0054] FIGs. 13A-13B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_53 against A549 lung cancer (FIG. 13A) and SK-OV-3 ovarian cancer (FIGs. 13B) cell lines at the effector:target ratio of 4:1. Irrelevant TCR recognized phosphorylated metabolites sensed in the context of butyrophilin 3A1 molecule. n = 3, bars represent S.E.M.

[0055] FIGs. 14A-14B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_54 against A549 lung cancer (FIG. 14A) and SK-OV-3 ovarian cancer (FIG. 14B) cell line at the effector:target ratio of 4:1. Irrelevant TCR recognized phosphorylated metabolites sensed in the context of butyrophilin 3A1 molecule. n = 3, bars represent S.E.M.

[0056] FIGs. 15A-15C show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_73 against MDA-MB-231 breast cancer (FIG. 15A), A375 melanoma (FIG. 15B) and SK-OV-3 ovarian cancer (FIG. 15C) cell lines at the effector:target ratio of 4:1. Irrelevant gene is truncated EGFR. n = 3, bars represent S.E.M.

[0057] FIGs. 16A-16C show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_52 against MDA-MB-231 breast cancer (FIG. 16A), A375 melanoma (FIG. 16B) and SK-OV-3ovarian cancer (FIG. 16C) cell lines at the effector:target ratio of 4:1. Irrelevant gene is truncated EGFR. n = 3, bars represent S.E.M.

[0058] FIGs. 17A-17C show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_29 against MDA-MB-231 breast cancer (FIG. 17A), A375 melanoma (FIG. 17B) and SK-OV-3 ovarian cancer cell lines at the effector:target ratio of 4:1. Irrelevant gene is truncated EGFR. n = 3, bars represent S.E.M.Attorney Docket No.: 304952000240

[0059] FIGs. 18A-18B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with TCR_50 against MDA-MB-231 breast cancer (FIG. 18A) and A375 melanoma (FIG. 18B) cell line at the effector:target ratio of 4:1. Irrelevant gene is truncated EGFR. n = 3, bars represent S.E.M.

[0060] FIG. 19 shows cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs, a negative control MAGE-A4 specific αβ TCR and a positive control HER2 specific CAR against MRC5 lung fibroblasts at the effector:target ratio of 4:1 after 72 h of co-incubation. n = 3, bars represent S.E.M.

[0061] FIGs. 20A-20B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs against a wild-type (WT) or B2M- knockout SK-OV-3 ovarian cancer cells (FIG. 20A) or MDA-MB-231 breast cancer cells (FIG. 20B) at the effector:target ratio of 4:1 after 72 h of co-incubation. n = 3, bars represent S.E.M.

[0062] FIGs. 21A-21D show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs against breast cancer cells (MDA-MB- 231) at the specified effector:target ratios after 72 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition) or a TCR and LTBR (TCR + LTBR condition). TCRs tested include TCR_73 (FIG. 21A), TCR_52 (FIG. 21B), TCR_29 (FIG. 21C), and TCR_61 (FIG. 21D). n = 3, bars represent S.E.M.

[0063] FIG. 22 shows interferon-γ (IFNγ) secretion by healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with breast cancer cells (MDA-MB-231) at the effector:target ratio of 8:1 after 24 h of co-incubation. As indicated, T cells were co-transduced to express a TCR and an irrelevant gene (TCR condition) or a TCR and LTBR (TCR + LTBR condition). n = 3, bars represent S.E.M.

[0064] FIGs. 23A-23B show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with lung cancer cells (A549) at the effector:target ratio of 8:1 after 72 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), a TCR and LTBR, a TCR and CD80 or a TCR and 4-1BBL. TCRs tested include TCR_73 (FIG. 23A) and TCR_61 (FIG. 23B). n = 3, bars represent S.E.M.Attorney Docket No.: 304952000240

[0065] FIGs. 24A-24D show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with lung cancer cells (A549) at the effector:target ratio of 8:1 after 64 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), or a TCR and LTBR. TCRs tested include TCR_29 (FIG. 24A), TCR_52 (FIG. 24B), TCR_61 (FIG. 24C), and TCR_73 (FIG. 24D). n=3, bars represent S.E.M.

[0066] FIGs. 25A-25D show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with breast cancer cells (BT529) at the effector:target ratio of 8:1 after 96 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), or a TCR and LTBR. TCRs tested include TCR_29 (FIG. 25A), TCR_52 (FIG. 25B), TCR_61 (FIG. 25C), and TCR_73 (FIG. 25D). n=3, bars represent S.E.M.

[0067] FIGs. 26A-26E show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with colorectal cancer cells (HT29) at the effector:target ratio of 8:1 after 96 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), or a TCR and LTBR. TCRs tested include TCR_29 (FIG. 26A), TCR_50 (FIG. 26B), TCR_52 (FIG. 26C), TCR_61 (FIG. 26D), and TCR_73 (FIG. 26E). n=3, bars represent S.E.M.

[0068] FIGs. 27A-27D show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with colorectal cancer cells (HCT116) at the effector:target ratio of 8:1 after 64 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), or a TCR and LTBR. TCRs tested include TCR_29 (FIG. 27A), TCR_52 (FIG. 27B), TCR_61 (FIG. 27C), and TCR_73 (FIG. 27D). n=3, bars represent S.E.M.

[0069] FIGs. 28A-28D show cytotoxic activity of healthy donor derived CD3+ T cells transduced with identified cancer-specific γδ TCRs co-incubated with lung cancer cells (NCI- 1975) at the effector:target ratio of 8:1 after 64 h of co-incubation. As indicated, T cells were engineered to express an irrelevant gene (truncated EGFR), or co-transduced to express a TCR and an irrelevant gene (TCR condition), a TCR and LTBR. TCRs tested includeAttorney Docket No.: 304952000240 TCR_29 (FIG. 28A), TCR_52 (FIG. 28B), TCR_61 (FIG. 28C), and TCR_73 (FIG. 28D). n=3, bars represent S.E.M. DETAILED DESCRIPTION

[0070] All publications, comprising patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0071] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. I. DEFINITIONS

[0072] As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0073] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0074] Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; Band C; A (alone); B (alone); and C (alone).

[0075] The term “nucleic acid” or “polynucleotide” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar as the reference nucleic acid andAttorney Docket No.: 304952000240 are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991): Qhtsuka et al, J. Biol. Chem. 260:2605-2608 (1985); and Rossolim et af., Mol. Cell. Probes 8:91-98 (1994)).

[0076] The terms “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence” are used interchangeably and refer to a contiguous nucleic acid sequence. The sequence can be either single stranded or double stranded DNA or RNA, e.g., an mRNA.

[0077] Nucleic acids described herein can be cloned using routine molecular biology techniques, or generated de novo by DNA synthesis, which can be performed using routine procedures by service companies having business in the field of DNA synthesis and / or molecular cloning (e.g. GeneArt, GenScript, Life Technologies, Eurofins). The nucleic acid sequences encoding aspects of a CRlSPR-Cas editing system described herein are assembled and placed into any suitable genetic element, e.g., naked DNA, phage, transposon, cosmid, episome, etc., which transfers the sequences carried thereon to a host cell, e.g., for generating non-viral delivery systems (e.g., RNA-based systems, naked DNA, or the like), or for generating viral vectors in a packaging host cell, and / or for delivery to a host cells in a subject. In certain embodiments, the genetic element is a vector. In one embodiment, the genetic element is a plasmid. The methods used to make such engineered constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Green and Sambrook, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012).

[0078] The term “gene” can refer to a segment of DNA involved in producing or encoding a polypeptide chain. It may include regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons).

[0079] As used herein, the terms “coding region” and “region encoding” and grammatical variants thereof, refer to an open reading frame (ORF) in a polynucleotide that upon expression yields a polypeptide or protein.Attorney Docket No.: 304952000240

[0080] “Polypeptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. As used herein, the terms encompass amino acid chains of any length, including full-length proteins, wherein the amino acid residues are linked by covalent peptide bonds.

[0081] The term “encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA, and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.

[0082] Unless otherwise specified, a “nucleic acid sequence encoding an amino acid sequence” includes all nucleic acid sequences that are degenerate versions of each other and that encode the same amino acid sequence. A nucleic acid sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some versions contain an intron(s).

[0083] The term “expression” is used herein in its broadest meaning and comprises the production of RNA, of protein, or of both RNA and protein. Expression may be transient or may be stable.

[0084] The terms “expressing” and “overexpression” refer to increasing the expression of a gene or protein. The terms refer to an increase in expression, for example, in increase in the amount of mRNA or protein expressed in a T cell, other lymphocyte or host cell, of at least 10%, as compared to a reference control level.

[0085] The term “autologous” refer to any material derived from the same subject to whom it is later to be re-introduced.

[0086] The term “exogenous” refers to any material introduced from or produced outside an organism, cell, tissue, or system.

[0087] The term “expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitroAttorney Docket No.: 304952000240 expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses) that incorporate the recombinant polynucleotide.

[0088] The term “regulatory element” or “regulatory sequence” refers to expression control sequences which are contiguous with the nucleic acid sequence of interest and expression control sequences that act in trans or at a distance to control the nucleic acid sequence of interest. As described herein, regulatory elements comprise but are not limited to: promoter; enhancer; transcription factor; transcription terminator; efficient RNA processing signals such as splicing and polyadenylation signals (polyA); sequences that stabilize cytoplasmic mRNA, for example Woodchuck Hepatitis Virus (WHP) Posttranscriptional Regulatory Element (WPRE); sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. Also, see Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Regulatory sequences include those which direct constitutive expression of a nucleic acid sequence in many types of target cell and those which direct expression of the nucleic acid sequence only in certain target cells (e.g., tissue-specific regulatory sequences).

[0089] A “promoter” is one or more a nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes necessary nucleic acid sequences near the start site of transcription, such as, in the case of a polymerase II type promoter, a TATA element. A promoter also optionally includes distal enhancer or repressor elements, which can be located as much as several thousand base pairs from the start site of transcription. The term "constitutive" when referring to a promoter specifies a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell. The term “inducible” or “regulatable” when referring to a promoter specifies a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell. In certain embodiments, the inducible promoter is activated in response to T cell stimulation. In certain embodiments, the promoter is an NFAT, APl, NFKB, or IRF4 promoter. The term “tissue- specific” when referring to a promoter specifies a nucleotide which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in aAttorney Docket No.: 304952000240 cell substantially only if the cell is a cell of the tissue type corresponding to the promoter. Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. Exemplary promoters include the CMV IE gene, EF-la., ubiquitin C, or phosphoglycerokinase (PGK) promoters.

[0090] The term “operably linked” or refers to functional linkage between one or more regulatory sequences and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other and, where necessary to join two protein coding regions, are in the same reading frame.

[0091] The term “lentivirus” refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.

[0092] In certain embodiments, one or more genes are encoded by a nucleic acid sequence that is delivered to a host cell by a vector or a viral vector, of which many are known and available in the art. In one embodiment, provided is a vector comprising an expression cassette as described herein. In one embodiment, a vector is a non-viral vector. In another embodiment, a vector is a viral vector. A “viral vector” refers to a synthetic or artificial viral particle in which an expression cassette containing a nucleic acid sequence of interest is packaged in a viral capsid or envelope. Examples of viral vectors include but are not limited to lentivirus, adenoviruses, retroviruses (y- retroviruses and lentiviruses), poxviruses, adeno- associated viruses (AAVs), baculoviruses, simplex viruses. In one embodiment, the viral vector is replication defective. A “replication-defective virus” refers to a viral vector,Attorney Docket No.: 304952000240 wherein any viral genomic sequences also packaged within the viral capsid or envelope are replication-deficient, i.e., they cannot generate progeny virions but retain the ability to infect cells.

[0093] The term “lentiviral vector” refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009). Other examples of lentivirus vectors that may be used in the clinic, include but are not limited to, e.g., the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAX™ vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art.

[0094] In certain embodiments, the vector is a non-viral plasmid that comprises an expression cassette described herein, e.g., naked DNA, naked plasmid DNA, RNA, and mRNA; coupled with various compositions and nano particles, including, e.g., micelles, liposomes, cationic lipid - nucleic acid compositions, poly-glycan compositions and other polymers, lipid and / or cholesterol-based - nucleic acid conjugates, and other constructs such as are described herein. See, e.g., X. Su et al, Mol. Pharmaceutics, 2011, 8 (3), pp 774-787; web publication: March 21, 2011; WO2013 / 182683, WO 2010 / 053572 and WO 2012 / 170930, all of which are incorporated herein by reference.

[0095] Plasmids, other cloning and expression vectors, properties thereof, and constructing / manipulating methods thereof that can be used in accordance with the present invention are readily apparent to those of skill in the art. In one embodiment, an expression cassette as described herein is engineered into a suitable genetic element (a vector) useful for generating viral vectors and / or for introduction to a host cell, e.g., naked DNA, phage, transposon, cosmid, episome, etc., which transfers the sequences carried thereon. The selected vector may be delivered by any suitable method, including transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion. The methods used to make such constructs are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY.

[0096] The term “transfected” refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” cell is one which has been transfected with exogenous nucleic acid. The includes the primary subject cell and its progeny.Attorney Docket No.: 304952000240

[0097] As used herein, “transient” refers to expression of a non-integrated transgene for a period of hours, days or weeks, wherein the period of time of expression is less than the period of time for expression of the gene if integrated into the genome or contained within a stable plasmid replicon in the host cell.

[0098] RNA or DNA can be introduced into target cells using any of a number of different methods, for instance, commercially available methods which include, but are not limited to, electroporation (Amaxa Nucleofector-11 (Amaxa Biosystems, Cologne, Germany)), (ECM 830 (BTX) (Harvard Instruments, Boston, Mass.) or the Gene Pulser II (BioRad, Denver, Colo.), Multiporator (Eppendorf, Hamburg Germany), cationic liposome mediated transfection using lipofection, polymer encapsulation, peptide mediated transfection, or biolistic particle delivery systems such as “gene guns” (see, for example, Nishikawa, et al. Hum Gene Ther., 12(8):861-70 (2001). II. OVERVIEW

[0099] Provided herein are modified lymphocyte comprising an exogenous nucleic acid encoding an engineered cancer reactive T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain. The cancer reactive γδ-TCRs disclosed herein provide a novel and effective therapeutic tool to kill cancer cells and treat cancer in individuals. Provided herein is the first demonstration that unconventional T cells from cancer patients express TCRs with broad cancer specificity. This broad cancer specificity enables the γδ TCRs disclosed herein to effectively kill cancer cells from multiple distinct cancer types. Also provided herein are methods to identify cancer reactive γδ TCRs from γδ T cells isolated from individuals with cancer. These methods provide the significant benefit of identifying the specific cancer type with which a given γδ TCR is reactive against. Such methods offer significant promise to develop engineered γδ TCRs with specific cancer reactivity. The modified lymphocytes comprising the engineered γδ TCRs therefore address an important therapeutic gap yet to be addressed using unconventional T cells.

[0100] Provided herein is the first demonstration of the utility of MHC-independent TCRs as therapeutic agents for cancer by genetically introducing them into recipient T cells. The forced expression of MHC-independent TCRs directs engineered T cells to kill cancer cells from multiple different indications while sparing healthy cells. Through genetic knockout of the MHC-I complex in target cancer cells, the independence of these TCRs isAttorney Docket No.: 304952000240 demonstrated, expanding their utility to the entire patient population expressing the TCR targets regardless of the MHC variant. Provided herein is a demonstration that the potency of these TCRs can be enhanced by co-expression with certain additional genes that act on the TCR co-stimulatory pathway or otherwise enhance T cell functions. III. MODIFIED LYMPHOCYTES A. Engineered TCRs

[0101] Provided herein are engineered T cell receptors (TCRs) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain. The extracellular antigen binding domain, the transmembrane domain, and the intracellular domain of the TCR-γ chain and the TCR-δ chain may be any one of the extracellular antigen binding domains, the transmembrane domains, and the intracellular domains described herein.

[0102] In some embodiments, the TCR-γ chain binds to the TCR-δ chain to form a γδ-TCR comprising a functional extracellular antigen binding domain formed from the TCR-γ extracellular antigen binding domain and the TCR-δ extracellular antigen binding domain. In some embodiments the binding specificity and affinity of the γδ-TCR is established by the functional interface formed when the TCR-γ extracellular antigen binding domain and the TCR- δ extracellular antigen binding domain dimerize.

[0103] In some embodiments, the TCR comprises a Vδ1+ chain, a Vδ2+chain, or a Vδ3+ chain. In some embodiments, the TCR comprises a Vδ1+ chain. In some embodiments, the TCR comprises a Vδ2+ chain. In some embodiments, the TCR comprises a Vδ3+ chain.

[0104] In some embodiments, the TCR is a Vγ9Vδ2 gamma-delta TCR. In some embodiments, the TCR comprise a Vγ9 chain.

[0105] In some embodiments, the TCR is a non-Vγ9Vδ2 gamma-delta TCR. In some embodiments, the TCR is a Vδ1+, a Vγ9-Vδ2+, or a Vδ3+ gamma-delta TCR.

[0106] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen comprises a CDR1, a CDR2, and a CDR3 comprising an amino acid sequence set forth in Table 2. In some embodiments, the TCR- δ extracellular antigen binding domain comprises a CDR1, a CDR2, and a CDR3 comprising an amino acid sequence set forth in Table 3.Attorney Docket No.: 304952000240

[0107] In some embodiments, the engineered TCR comprises a TCR-γ chain and a TCR-δ chain. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in Table 4.

[0108] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:301, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:302, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:303. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:601, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:602. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:601, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:602.

[0109] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:6, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:304, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:305, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:306. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:603, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:604. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:603, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:604.

[0110] In some embodiments, the engineered comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments,Attorney Docket No.: 304952000240 the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:7, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:8, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:9, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:307, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:308, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:309. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:605, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:606. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:605, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:606.

[0111] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:10, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:11, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:12, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:310, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:311, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:312. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:607, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:608. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:607, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:608.

[0112] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:13, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:15, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth SEQ ID NO:313, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:314, and a CDR3 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:315. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:609, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:610. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:609, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:610.

[0113] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:16, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:17, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:18, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:316, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:317, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:318. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:611, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:612. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:611, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:612.

[0114] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:19, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:20, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:21, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:319, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:320, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:321. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:613, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:614. In some embodiments, the TCR-γ chain comprises the amino acid sequence set in SEQ ID NO:613, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:614.Attorney Docket No.: 304952000240

[0115] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:22, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:23, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:24, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:322, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:323, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:324. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:615, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:616. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:615, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:616.

[0116] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:325, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:326, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:327. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:617, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:618. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:617, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:618.

[0117] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:28, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:29, and a CDR3 the amino acid sequence set forth in SEQ ID NO:30, and the TCR-δ extracellular antigen binding domain comprises a CDR1Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:328, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:329, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:330. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:619, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:620. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:619, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:620.

[0118] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:32, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:33, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:331, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:332, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:333. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:621, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:622. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:621, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:622.

[0119] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:36, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:334, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:336. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:623, and a CDR1, a and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:624. In some embodiments, the TCR-γAttorney Docket No.: 304952000240 chain comprises the amino acid sequence set forth in SEQ ID NO:623, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:624.

[0120] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:37, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:38, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:39, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:337, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:338, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:339. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:625, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:626. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:625, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:626.

[0121] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:42, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:340, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:341, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:342. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:627, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:628. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:627, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:628.

[0122] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:43, a CDR2 comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:45, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:343, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:344, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:345. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:629, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:630. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:629, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:630.

[0123] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:346, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:347, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:348. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:631, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:632. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:631, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:632.

[0124] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:49, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:50, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:51, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:349, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:350, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:351. In the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:633, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:634. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:633, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:634.

[0125] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:53, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:54, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:352, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:353, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:354. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:635, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:636. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:635, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:636.

[0126] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:55, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:56, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:57, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:355, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:356, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:357. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:637, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:638. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:637, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:638.

[0127] In some embodiments, the engineered comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments,Attorney Docket No.: 304952000240 the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:58, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:59, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:60, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:358, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:359, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:360. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:639, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:640. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:639, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:640.

[0128] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:61, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:62, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:63, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:361, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:362, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:363. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:641, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:642. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:641, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:642.

[0129] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:64, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:65, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:66, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth SEQ ID NO:364, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:365, and a CDR3 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:366. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:643, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:644. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:643, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:644.

[0130] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:67, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:68, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:69, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:367, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:368, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:369. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:645, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:646. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:645, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:646.

[0131] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:70, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:71, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:72, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:370, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:371, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:372. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:647, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:648. In some embodiments, the TCR-γ chain comprises the amino acid sequence set in SEQ ID NO:647, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:648.Attorney Docket No.: 304952000240

[0132] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:73, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:74, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:75, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:373, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:374, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:375. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:649, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:650. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:649, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:650.

[0133] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:76, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:77, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:78, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:376, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:377, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:378. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:651, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:652. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:651, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:652.

[0134] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:79, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:80, and a CDR3 the amino acid sequence set forth in SEQ ID NO:81, and the TCR-δ extracellular antigen binding domain comprises a CDR1Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:379, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:380, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:381. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:653, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:654. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:653, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:654.

[0135] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:82, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:83, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:84, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:382, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:383, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:384. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:655, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:656. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:655, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:656.

[0136] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:86, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:385, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:386, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:387. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:657, and a CDR1, a and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:658. In some embodiments, the TCR-γAttorney Docket No.: 304952000240 chain comprises the amino acid sequence set forth in SEQ ID NO:657, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:658.

[0137] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:88, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:89, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:90, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:388, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:389, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:390. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:659, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:660. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:659, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:660.

[0138] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:91, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:92, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:93, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:391, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:392, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:393. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:661, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:662. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:661, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:662.

[0139] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:94, a CDR2 comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:95, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:96, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:394, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:395, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:396. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:663, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:664. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:663, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:664.

[0140] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:97, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:98, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:99, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:397, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:398, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:399. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:665, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:666. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:665, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:666.

[0141] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:100, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:101, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:102, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:400, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:401, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:402. In the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:667, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:668. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:667, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:668.

[0142] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:103, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:104, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:105, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:403, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:404, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:405. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:669, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:670. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:669, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:670.

[0143] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:106, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:107, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:108, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:406, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:407, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:408. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:671, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:672. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:671, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:672.

[0144] In some embodiments, the comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments,Attorney Docket No.: 304952000240 the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:109, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:110, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:111, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:409, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:410, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:411. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:673, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:674. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:673, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:674.

[0145] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:112, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:113, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:114, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:412, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:413, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:414. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:675, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:676. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:675, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:676.

[0146] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:115, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:116, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:117, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth SEQ ID NO:415, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:416, and a CDR3 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:417. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:677, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:678. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:677, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:678.

[0147] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:118, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:119, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:120, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:418, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:419, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:420. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:679, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:680. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:679, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:680.

[0148] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:121, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:122, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:123, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:421, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:422, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:423. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:681, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:682. In some embodiments, the TCR-γ chain comprises the amino acid sequence set in SEQ ID NO:681, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:682.Attorney Docket No.: 304952000240

[0149] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:124, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:125, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:126, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:424, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:425, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:426. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:683, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:684. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:683, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:684.

[0150] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:127, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:128, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:129, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:427, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:428, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:429. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:685, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:686. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:685, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:686.

[0151] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:130, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:131, and a CDR3 the amino acid sequence set forth in SEQ ID NO:132, and the TCR-δ extracellular antigen binding domain comprises a CDR1Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:430, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:431, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:432. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:687, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:688. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:687, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:688.

[0152] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:133, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:134, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:135, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:433, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:434, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:435. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:689, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:690. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:689, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:690.

[0153] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:136, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:137, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:138, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:436, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:437, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:438. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:691, and a CDR1, a and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:692. In some embodiments, the TCR-γAttorney Docket No.: 304952000240 chain comprises the amino acid sequence set forth in SEQ ID NO:691, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:692.

[0154] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:139, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:140, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:141, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:439, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:440, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:441. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:693, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:694. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:693, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:694.

[0155] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:142, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:143, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:144, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:442, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:443, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:444. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:695, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:696. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:695, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:696.

[0156] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:145, a CDR2 comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:146, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:147, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:445, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:446, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:447. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:697, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:698. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:697, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:698.

[0157] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:148, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:149, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:150, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:448, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:449, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:450. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:699, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:700. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:699, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:700.

[0158] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:151, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:152, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:153, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:451, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:452, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:453. In the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:701, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:702. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:701, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:702.

[0159] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:454, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:455, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:456. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:703, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:704. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:703, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:704.

[0160] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:457, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:458, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:459. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:705, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:706. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:705, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:706.

[0161] In some embodiments, the engineered comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments,Attorney Docket No.: 304952000240 the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:460, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:461, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:462. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:707, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:708. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:707, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:708.

[0162] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:163, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:164, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:165, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:463, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:464, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:465. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:709, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:710. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:709, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:710.

[0163] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:166, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:167, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:168, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth SEQ ID NO:466, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:467, and a CDR3 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:468. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:711, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:712. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:711, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:712.

[0164] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:169, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:170, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:171, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:469, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:470, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:471. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:713, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:714. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:713, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:714.

[0165] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:472, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:473, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:474. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:715, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:716. In some embodiments, the TCR-γ chain comprises the amino acid sequence set in SEQ ID NO:715, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:716.Attorney Docket No.: 304952000240

[0166] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:175, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:176, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:177, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:475, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:476, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:477. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:717, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:718. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:717, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:718.

[0167] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:178, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:179, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:478, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:479, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:480. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:719, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:720. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:719, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:720.

[0168] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a CDR3 the amino acid sequence set forth in SEQ ID NO:183, and the TCR-δ extracellular antigen binding domain comprises a CDR1Attorney Docket No.: 304952000240 comprising the amino acid sequence set forth in SEQ ID NO:481, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:482, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:483. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:721, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:722. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:721, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:722.

[0169] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:184, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:185, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:186, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:484, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:485, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:486. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:723, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:724. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:723, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:724.

[0170] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:187, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:188, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:189, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:487, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:488, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:489. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:725, and a CDR1, a and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:726. In some embodiments, the TCR-γAttorney Docket No.: 304952000240 chain comprises the amino acid sequence set forth in SEQ ID NO:725, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:726.

[0171] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:190, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:191, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:192, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:490, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:491, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:492. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:727, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:728. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:727, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:728.

[0172] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:193, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:194, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:195, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:493, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:494, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:495. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:729, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:730. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:729, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:730.

[0173] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:196, a CDR2 comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:197, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:198, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:496, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:497, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:498. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:731, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:732. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:731, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:732.

[0174] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:199, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:200, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:201, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:499, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:500, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:501. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:733, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:734. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:733, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:734.

[0175] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:202, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:203, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:204, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:502, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:503, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:504. In the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence setAttorney Docket No.: 304952000240 forth in SEQ ID NO:735, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:736. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:735, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:736.

[0176] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:205, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:206, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:207, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:505, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:506, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:507. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:737, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:738. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:737, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:738.

[0177] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:208, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:209, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:210, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:508, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:509, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:510. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:739, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:740. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:739, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:740.

[0178] In some embodiments, the engineered comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments,Attorney Docket No.: 304952000240 the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:211, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:212, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:213, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:511, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:512, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:513. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:741, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:742. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:741, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:742.

[0179] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:214, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:215, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:216, and the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:514, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:515, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:516. In some embodiments, the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:743, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:744. In some embodiments, the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:743, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:744.

[0180] In some embodiments, the engineered TCR comprises a TCR-γ extracellular antigen binding domain and a TCR-δ extracellular antigen binding domain. In some embodiments, the TCR -γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:217, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:218, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:219, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth SEQ ID NO:517, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:518, and a CDR3 comprising the amino acidAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:519. In some embodiments, the TCR -γ chain comprises the amino acid sequence set forth in SEQ ID NO:745, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:746.

[0181] In some embodiments, the engineered TCR comprises a transmembrane domain. In some embodiments, the transmembrane domain connects the antigen binding domain to the intracellular domain. In some embodiments, the transmembrane domain comprises an amino acid sequence set forth in SEQ ID NOs:551-552. In some embodiments, the TCR-γ chain comprises a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:551. In some embodiments, the TCR-δ chain comprises a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:552. TCR-γ Transmembrane Domain SEQ ID NO:551 YYMYLLLLLKSVVYFAIITCCLL TCR-δ Transmembrane Domain SEQ ID NO: 552 LTVLGLRMLFAKTVAVNFLLT

[0182] In some embodiments, the engineered TCR comprises an intracellular domain. In some embodiments, the intracellular domain comprises an amino acid sequence set forth in SEQ ID NOs:561-562. In some embodiments, the TCR-γ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:561. In some embodiments, the TCR-δ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:562. TCR-γ Intracellular Domain SEQ ID NO:561 RRTAFCCNGEKS TCR-δ Intracellular Domain SEQ ID NO: 562 AKLFFL

[0183] In some embodiments, the engineered TCR recognizes an antigen specifically expressed by cancer cells or tumor cells. In some embodiments, the antigen is not expressed by healthy and / or non-cancerous cells. In some embodiments, the engineered TCR does not stimulate an autoimmune response in cancer patients.

[0184] In some embodiments, the engineered recognizes an antigen in an MHC- independent manner. For example, an antigen can be presented in an MHC-independentAttorney Docket No.: 304952000240 manner if the antigen is not bound to MHC-I on the surface of a cell. In some embodiments, the binding of the engineered TCR to the antigen does not require antigen presentation mediated by MHC-I. For example, the engineered TCR can still bind the antigen expressed on a cell lacking functional MHC-I. In some embodiments, the antigen is expressed by a cancer cell or a tumor cell in an MHC-I-independent manner. In some embodiments, the antigen is expressed by a cancer cell or a tumor cell with decreased or no MHC-I expression. B. Nucleic Acids and Vectors

[0185] In some embodiments, the modified lymphocyte comprises an exogenous nucleic acid encoding the gamma-delta TCR. In some embodiments, the exogenous nucleic acid comprises an expression cassette comprising a promoter and the nucleic acid encoding any of the cancer reactive γδ-TCRs described herein. In some embodiments the exogenous nucleic acid comprises a TCR-γ chain and the TCR-δ chain.

[0186] In some embodiments, a modified lymphocyte is engineered to express an increased level of an immunosuppressive resistance gene. In some embodiments, the immunosuppressive resistance gene is endogenously expressed by the lymphocyte. In some embodiments, the immunosuppressive resistance gene is not naturally expressed by the lymphocyte. In some embodiments, the target cell is a tumor cell or cancer cell. In some embodiments, expression of the immunosuppressive resistance gene in a modified lymphocyte results in increased proliferation and / or increased effector function of the modified lymphocyte in in vitro or in vivo cell proliferation relative to a lymphocyte that does not express the immunosuppressive resistance gene. In some embodiments, expression of the immunosuppressive resistance gene in a modified lymphocyte results in increased tumor cell-killing capacity relative to a lymphocyte that does not express the immunosuppressive resistance gene. In some embodiments, expression of the immunosuppressive resistance gene in a modified lymphocyte results in increased lymphocyte function in an immunosuppressive tumor microenvironment. In some embodiments, the immunosuppressive resistance gene is selected from the group consisting of TNFRSF1A (TNFR1 / CD120a) (Gene Accession Number NM_001065), TNFRSF1B (TNFR2 / CD120b) (Gene Accession Number NM_001066), TNFRSF3 (LTBR) (Gene Accession Number NM_002342), TNFRSF4 (OX40 / CD134) (Gene Accession Number NM_003327), TNFRSF5 (CD40) (Gene Accession Number NM_001250), TNFRSF6 (Fas / CD95) (Gene Accession Number NM_000043), TNFRSF7 (CD27) (Gene Accession Number NM_001242), TNFRSF8 (CD30) Accession Number NM_001243),Attorney Docket No.: 304952000240 TNFRSF9 (4-1BB / CD137) (Gene Accession Number NM_001561), TNFRSF10A (TRAIL- R1 / DR4) (Gene Accession Number NM_003844), TNFRSF10B (TRAIL-R2 / DR5) (Gene Accession Number NM_003842), TNFRSF10C (TRAIL-R3 / DcR1) (Gene Accession Number NM_003841), TNFRSF10D (TRAIL-R4 / DcR2) (Gene Accession Number NM_003840), TNFRSF11A (RANK) (Gene Accession Number NM_003839), TNFRSF11B (OPG / Osteoprotegerin) (Gene Accession Number NM_002546), TNFRSF12A (TWEAK- R / Fn14) (Gene Accession Number NM_016639), TNFRSF13B (TACI) (Gene Accession Number NM_012452), TNFRSF13C (BAFF-R) (Gene Accession Number NM_001192), TNFRSF14 (HVEM) (Gene Accession Number NM_003820), TNFRSF16 (NGFR / p75NTR) (Gene Accession Number NM_002507), TNFRSF17 (BCMA) (Gene Accession Number NM_001192), TNFRSF18 (GITR) (Gene Accession Number NM_004195), TNFRSF19 (TROY) (Gene Accession Number NM_018647), TNFRSF21 (DR6) (Gene Accession Number NM_014452), and TNFRSF25 (DR3 / TRAMP) (Gene Accession Number NM_003790). Gene Accession Numbers are catalogued, for example, at ncbi.nlm.nih.gov. In some embodiments, the immunosuppressive resistance gene is LTBR.

[0187] As used herein, the term “expression cassette” refers to a nucleic acid molecule which encodes one or more biologically useful nucleic acid sequences (e.g., a gene cDNA encoding a protein, receptor, enzyme or other useful gene product, mRNA, etc.) and regulatory sequences operably linked thereto which direct or modulate transcription, translation, and / or expression of the nucleic acid sequence(s) and its gene product(s). Such regulatory sequences typically include, e.g., one or more of a promoter, an enhancer, an intron, a Kozak sequence, a polyadenylation sequence, and a TATA signal. The expression cassette may contain regulatory sequences upstream (5’ to) of the gene sequence, e.g., one or more of a promoter, an enhancer, an intron, etc., and one or more of an enhancer, or regulatory sequences downstream (3’ to) a gene sequence, e.g., 3’ untranslated region comprising a polyadenylation site, among other elements. Thus, in addition to the coding sequence for the effector enhancing gene (and / or the CAR or TCR) the expression cassette may also include expression control sequences.

[0188] In some embodiments, the expression control sequences include a promoter. In some embodiments, its it is desirable to utilize a promoter having high transcriptional activity. Certain strong constitutive promoters are known in the art and include, without limitation, the CMV promoter, the EF-la promoter, EFS promoter, CBG promoter, CB7 promoter, hPGK, RPBSA, WAS promoter, etc. Alternatively, promoters, such as regulatable (inducible) promoters [see, e.g., WO 2011 / 126808 and WO 2013 / 049493, all of which are hereinAttorney Docket No.: 304952000240 incorporated by reference in their entireties], or a promoter responsive to physiologic cues may be utilized. In some embodiments, the promoter is selected from the group consisting of cytomegalovirus (CMV) immediate-early enhancer, chicken beta-actin (CAG), human beta- actin, elongation factor 1α (EF1α), SV40, ubiquitin C (UbC), tetracycline response element (TRE), and PGK. In some embodiments, the promoter is a short EF-1α promoter. In some embodiments, the promoter drives expression of the nucleic acid encoding the γδ-TCR at levels sufficient to enable a T cell response when exposed to an antigen recognized by the γδ- TCR. In some embodiments, it is desirable to utilize a promoter that is responsive to activation of the T cell. Such promoters include, without limitation NFAT, NFKB and API promoters. In some embodiments, the promoter is a ubiquitous promoter. In some embodiments, the promoter drives constitutive expression of the TCR. In some embodiments, the promoter is an inducible promoter.

[0189] The expression cassette may also include, in certain embodiments, one or more IRES or 2A sequences to allow for expression of multiple coding sequences from the same expression cassette.

[0190] In some embodiments, the expression cassette further comprises an antibiotic resistance gene. In some embodiments, the antibiotic resistance gene is a puromycin or blasticidin resistance gene.

[0191] In some embodiments, the expression cassette further comprises polynucleotides encoding an intracellular enzyme, a fluorescent protein, and / or a surface expressed safety switch protein. In some embodiments, the expression cassette further comprises polynucleotides encoding an immunosuppressive resistance gene. In some embodiments, the surface expressed safety switch protein comprises full length CD20, HER2, EGFR, and / or NGFR, or a functional fragment thereof.

[0192] Construction of such cassettes and vectors are known in the art. See, e.g., Sack et al. Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns. Cell. 2018 Apr 5;173(2):499-514.e2 and Yang et al, A public genome- scale lentiviral expression library of human ORFs, Nat Methods. 2011 Aug; 8(8): 659-661, which are incorporated herein by reference.

[0193] In some embodiments, the expression cassette is integrated into the genome of the modified lymphocyte. In some embodiments, the expression cassette is integrated into a native TCR genomic locus of the modified lymphocyte (e.g. the gamma-delta TCR loci). In some embodiments, the expression cassette is into a safe harbor locus of the modified lymphocyte. In some embodiments, the safe harbor locus is selected from the groupAttorney Docket No.: 304952000240 consisting of AAVS1, hROSA26, and CCR5. In some embodiments, the expression cassette is randomly integrated into the genome of the modified lymphocyte. In some embodiments, the expression cassette is integrated into the genome of the modified lymphocyte by a transposon, a designer nuclease, or a CRISPR / Cas9 system.

[0194] In some embodiments, provided herein, are vectors comprising the expression cassette comprising the exogenous nucleic acid encoding the gamma-delta TCR. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is selected from the group consisting of lentivirus, adenovirus, retrovirus, and baculovirus.

[0195] In some embodiments, the vector is an episomal or non-integrating vector. In some embodiments, the episomal vector is a Simian virus 40 (SV40), Adenovirus, or Adeno- associated vector.

[0196] In some embodiments, the vector is a non-viral vector. In some embodiments, the non-viral vector is a plasmid. In some embodiments, the non-viral vector is delivered to a lymphocyte by electroporation, or cell squeezing. In some embodiments, the non-viral vector is encapsulated in nanoparticles or liposomes.

[0197] In some embodiments, the nucleic acid encoding the gamma-delta TCR comprises a codon-optimized nucleic acid sequence set forth in SEQ ID NOs:801-944. In some embodiments, the nucleic acid encoding the gamma-delta TCR comprises a codon-optimized nucleic acid sequence set forth in Table 5.

[0198] In some embodiments, the vector comprises, an EFS promoter, a Kozak sequence, a TCR-gamma V segment sequence, a TCR-gamma CDR3 sequence, a TCR-gamma J segment sequence, a TCR-gamma C1 segment sequence, a T2A sequence, a TCR-delta V segment sequence, a TCR-delta CDR3 sequence, a TCR-delta J segment sequence, a TCR-delta C segment sequence, a P2A sequence, and a Puromycin resistance gene sequence. In some embodiments, the vector further comprises a nucleotide sequence encoding a CAR or a TCR.

[0199] In some embodiments, the vector comprises, from 5’ to 3’ an EFS promoter, a Kozak sequence, a TCR-gamma V segment sequence, a TCR-gamma CDR3 sequence, a TCR- gamma J segment sequence, a TCR-gamma C1 segment sequence, a T2A sequence, a TCR- delta V segment sequence, a TCR-delta CDR3 sequence, a TCR-delta J segment sequence, a TCR-delta C segment sequence, a P2A sequence, and a Puromycin resistance gene sequence. In some embodiments, the vector further comprises a nucleotide sequence encoding a CAR or a TCR.

[0200] In some embodiments, the EFS comprises a nucleotide sequence set forth in SEQ ID NO:950. In some embodiments, the Kozak sequence comprises a nucleotideAttorney Docket No.: 304952000240 sequence set forth in SEQ ID NO:951. In some embodiments, the T2A sequence comprises a nucleotide sequence set forth in SEQ ID NO:956. In some embodiments, the P2A sequence comprises a nucleotide sequence set forth in SEQ ID NO:961. In some embodiments, the puromycin resistance gene comprises a nucleotide sequence set forth in SEQ ID NO:962. C. Lymphocytes

[0201] Provided herein are modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3, and wherein the modified lymphocyte is cancer reactive.

[0202] In some embodiments, the modified lymphocyte is a gamma-delta T cell. In some embodiments, the gamma-delta T cell is engineered to express an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3.

[0203] In some embodiments, the gamma-delta T cell expresses an endogenous γδTCR and further expresses an engineered γδTCR comprising a CDR1, a CDR2, and a CDR3 of a TCR- γ chain comprising an amino acid sequence set forth in Table 3 and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3.

[0204] In some embodiments, the modified lymphocyte is a CD3+ T cell. In some embodiments, the CD3+ T cell is a CD4+ T cell or a CD8+ T cell. In some embodiments, the modified lymphocyte is a CD3+ CD4+ T cell. In some embodiments, the modified lymphocyte is a CD3+ CD8+ T cell. In some embodiments, the a CD3+ CD4+ T cell is engineered to express an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR- δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain and a CDR1, a a CDR3 of a TCR-δ chain comprising anAttorney Docket No.: 304952000240 amino acid sequence set forth in Table 3. In some embodiments, the a CD3+ CD8+ T cell is engineered to express an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR- δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3.

[0205] In some embodiments, the gamma-delta T cell is engineered to remove the endogenous γδTCR locus and is further modified to express an engineered γδTCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3 and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3.

[0206] In some embodiments, the gamma-delta T cell is engineered to silence the endogenous γδTCR locus and is further modified to express an engineered γδTCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3 and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3.

[0207] In some embodiments, the modified lymphocyte is a primary human lymphocyte. In some embodiments, the primary human lymphocyte is isolated from a blood sample obtained from an individual.

[0208] In some embodiments, the modified lymphocyte is an autologous lymphocyte. In some embodiments, the autologous lymphocyte is isolated from a blood sample obtained from an individual, modified to express an engineered γδTCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3 and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3 and reintroduced to the same individual.

[0209] In some embodiments, the modified lymphocyte comprising the engineered γδTCR is cancer reactive. In some embodiments, the γδTCR comprises an extracellular antigen binding domain that recognizes a cancer antigen expressed in a cancer type, such as a solid cancer. In some embodiments, the cancer type is selected from the group consisting of lung, breast, pancreatic, colorectal, and ovarian cancer.

[0210] In some embodiments, the modified lymphocyte comprising the engineered γδTCR is not reactive with healthy or non-cancerous and / or tissue. In some embodiments, the modified lymphocyte comprises an engineered γδTCR that binds an antigen only expressedAttorney Docket No.: 304952000240 on cancer cells. In some embodiments, the modified lymphocyte comprises an engineered γδTCR that recognizes a target antigen that is not expressed on healthy human cells. In some embodiments, co-incubation of the modified lymphocyte comprising the engineered γδTCR with healthy human cells does not result in killing of the healthy human cells. In some embodiments, treatment of an individual with the modified lymphocyte comprising the engineered γδTCR does not result in an autoimmune reaction.

[0211] In some embodiments, the modified lymphocyte comprising the engineered γδTCR binds to an antigen in an MHC-independent manner. In some embodiments, modified lymphocyte comprises an engineered γδTCR that binds an antigen expressed by a cancer cell or a tumor cell in an MHC-independent manner. In some embodiments, MHC-independent expression is presentation of an antigen at a cell surface without the use of the MHC-I complex.

[0212] In some embodiments, the engineered γδTCR is reactive against a single cancer type. In some embodiments, the engineered γδTCR is reactive against lung cancer. In some embodiments, the engineered γδTCR is reactive against breast cancer. In some embodiments, the engineered γδTCR is reactive against pancreatic cancer. In some embodiments, the engineered γδTCR is reactive against colorectal cancer. In some embodiments, the engineered γδTCR is reactive against ovarian cancer.

[0213] In some embodiments, the engineered γδTCR is reactive against multiple cancer types. In some embodiments, the γδTCR is reactive against one, two, three, four, or five cancer types. In some embodiments, the cancer type is selected from the group consisting of lung, breast, pancreatic, colorectal, and ovarian cancer. In some embodiments, the engineered γδTCR is reactive against pancreatic, ovarian, lung, and breast cancer. In some embodiments, the engineered γδTCR is reactive against pancreatic, colorectal, lung, and breast cancer. In some embodiments, the engineered γδTCR is reactive against lung, breast, pancreatic, colorectal, and ovarian cancer.

[0214] In some embodiments, the modified lymphocyte comprises an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain and is modified to express an immunosuppressive resistance gene. The engineered γδTCR can be any one of those described, for example, in Section III.A. The immunosuppressive resistance gene can be any one of those described in Section III.B. In some embodiments, the immunosuppressive resistance gene is LTBR. In some embodiments, the modified lymphocyte comprises an engineered γδTCR comprising a CDR1, a and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3 and a CDR1, a CDR2, and a CDR3 of a TCR-δAttorney Docket No.: 304952000240 chain comprising an amino acid sequence set forth in Table 3 and is modified to express the immunosuppressive resistance gene LTBR. In some embodiments, the modified lymphocyte comprises the engineered γδTCR TCR_73 and is modified to express the immunosuppressive resistance gene LTBR. In some embodiments, the modified lymphocyte comprises the engineered γδTCR TCR_52 and is modified to express the immunosuppressive resistance gene LTBR. In some embodiments, the modified lymphocyte comprises the engineered γδTCR TCR_29 and is modified to express the immunosuppressive resistance gene LTBR. In some embodiments, the modified lymphocyte comprises the engineered γδTCR TCR_61 and is modified to express the immunosuppressive resistance gene LTBR. In some embodiments, the modified lymphocyte comprises the engineered γδTCR TCR_50 and is modified to express the immunosuppressive resistance gene LTBR.

[0215] In some embodiments, the modified lymphocyte further comprises a co-stimulatory protein or a functional portion thereof. In some embodiments, the modified lymphocyte expresses a co-stimulatory protein or a functional portion thereof. Expression of a co- stimulatory protein or a functional portion thereof can drive increased expansion, function, persistence, and / or antitumor activity of the modified lymphocyte. In some embodiments, expression of a co-stimulatory protein or functional portion thereof enhances the function of the engineered TCR in the modified lymphocyte. In some embodiments, expression of a co- stimulatory protein or functional portion thereof enhances cytotoxicity of the modified lymphocyte against cancer or tumor cells. In some embodiments, the functional portion of the co-stimulatory protein is a co-stimulatory domain that functions alone or as part of a fusion construct. In some embodiments, the co-stimulatory protein or the functional portion thereof is selected from the group consisting of CD80, CD86, ICOS-L, 4-1BBL, OX40L, CD70, CD40L, and TLR agonists. In some embodiments, the co-stimulatory protein or functional portion thereof is CD80. In some embodiments, the co-stimulatory protein or functional portion thereof is 4-1BBL. In some embodiments, the modified lymphocyte expresses the engineered TCR TCR_73 and the co-stimulatory protein CD80. In some embodiments, the modified lymphocyte expresses the engineered TCR TCR_73 and the co-stimulatory protein 4-1BBL. In some embodiments, the modified lymphocyte expresses the engineered TCR TCR_61 and the co-stimulatory protein CD80. In some embodiments, the modified lymphocyte expresses the engineered TCR TCR_61 and the co-stimulatory protein 4-1BBL.

[0216] In some embodiments, the modified lymphocyte comprises enhanced cytotoxicity towards a cancer cell type compared to the of an unmodified lymphocyte to the same cancer cell type. In some embodiments, the modified lymphocyte comprises at leastAttorney Docket No.: 304952000240 1.2-fold enhanced cytotoxicity towards a cancer cell type compared to the cytotoxicity of an unmodified lymphocyte to the same cancer cell type. In some embodiments, the modified lymphocyte comprises at about 1.2, about 1.5, about 1.7, about 2.0, about 2.5, about 5.0, or about 10-fold enhanced cytotoxicity towards a cancer cell type compared to the cytotoxicity of an unmodified lymphocyte to the same cancer cell type.

[0217] In some embodiments, the modified lymphocyte comprising an engineered TCR and immunosuppressive resistance gene comprises enhanced cytotoxicity towards a cancer cell type compared to the cytotoxicity of an unmodified lymphocyte to the same cancer cell type. In some embodiments, co-expression of the engineered TCR and the immunosuppressive resistance gene in the modified lymphocyte results in cytotoxicity towards a cancer cell type at a lower dose of the modified lymphocyte compared to the dose of a lymphocyte comprising only an engineered TCR required for cytotoxicity against the same cancer cell type. D. Compositions Comprising Modified Lymphocytes.

[0218] In one aspect, provided herein is a pharmaceutical composition comprising modified lymphocytes expressing any of the cancer reactive γδTCRs described herein. In some embodiments, the pharmaceutical composition comprises a plurality of modified lymphocytes expressing a single engineered γδTCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in SEQ ID NOs:601-744 and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in SEQ ID NOs:601-744. In some embodiments, the modified lymphocyte is a CD3+ T cell. In some embodiments, the modified lymphocyte is a CD4+ T cell or a CD8+ T cell. In some embodiments, the modified lymphocyte is a gamma-delta T cell. In some embodiments, the modified lymphocyte is a primary human lymphocyte. In some embodiments, the modified lymphocyte is an autologous lymphocyte.

[0219] In some embodiments, the composition is in the form of a liquid. In some embodiments, the liquid is a cellular suspension. In some embodiments, the liquid is useful for delivery by injection. In some embodiments, the liquid comprises a cell culture media. In some embodiments, a composition for administration by injection, in addition to the modified lymphocytes, contains one or more excipients selected from the group consisting of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer, and isotonic agent.Attorney Docket No.: 304952000240 IV. METHODS OF USING MODIFED LYMPHOCYTES

[0220] In some embodiments, provided herein are methods of killing cancer cells in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3, a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3, and wherein the modified lymphocyte is cancer reactive.

[0221] In other embodiments, provided herein are methods of treating cancer in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3, a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3, and wherein the modified lymphocyte is cancer reactive.

[0222] In other embodiments, provided herein are methods of treating cancer in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3, a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3, wherein the engineered TCR targets cancer cells that do not present antigens using MHC-I, and wherein the modified lymphocyte is cancer reactive.

[0223] In other embodiments, provided herein are methods of killing cancer cells in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid an engineered T cell receptor (TCR)Attorney Docket No.: 304952000240 comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 3, a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 3, wherein the engineered TCR targets cancer cells that do not present antigens using MHC-I, and wherein the modified lymphocyte is cancer reactive.

[0224] In other embodiments, provided herein are methods of treating cancer in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73, wherein the modified lymphocyte is cancer reactive, wherein the cancer is a solid cancer.

[0225] In other embodiments, provided herein are methods of killing cancer cells in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73, wherein the modified lymphocyte is cancer reactive, wherein the cancer cells are derived from a solid cancer.

[0226] In some embodiments, the solid cancer is an epithelial cancer. In some embodiments, the epithelial cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer. In some embodiments, the solid cancer is a melanoma.

[0227] In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_01. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_09. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_29. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_50. In some embodiments, the cancer is epithelial cancer and the engineered TCR is TCR_52. In some embodiments, the cancer is an epithelial cancer and the engineered TCR isAttorney Docket No.: 304952000240 TCR_53. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_54. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_58. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_61. In some embodiments, the cancer is an epithelial cancer and the engineered TCR is TCR_73.

[0228] In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_01. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_09. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_29. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_52. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_53. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_54. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_58. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_61. In some embodiments, the epithelial cancer is ovarian cancer and the engineered TCR is TCR_73.

[0229] In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_09. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_29. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_50. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_52. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_61. In some embodiments, the epithelial cancer is breast cancer and the engineered TCR is TCR_73.

[0230] In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_01. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_09. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_29. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_52. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_53. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_54. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_58. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_61. In some embodiments, the epithelial cancer is lung cancer and the engineered TCR is TCR_73.Attorney Docket No.: 304952000240

[0231] In some embodiments, the epithelial cancer is lung cancer, the engineered TCR is TCR_61, and the modified lymphocyte further expresses a co-stimulatory protein or functional portion thereof. In some embodiments, the epithelial cancer is lung cancer, the engineered TCR is TCR_73, and the modified lymphocyte further expresses a co-stimulatory protein or functional portion thereof. In some embodiments, the co-stimulatory protein is CD80. In some embodiments, the co-stimulatory protein is 4-1BBL.

[0232] In some embodiments, the epithelial cancer is pancreatic cancer and the engineered TCR is TCR_09.

[0233] In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_09. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_29. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_50. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_52. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_61. In some embodiments, the epithelial cancer is colorectal cancer and the engineered TCR is TCR_73.

[0234] In some embodiments, the solid cancer is a melanoma and the engineered TCR is TCR_29. In some embodiments, the solid cancer is a melanoma and the engineered TCR is TCR_50. In some embodiments, the solid cancer is a melanoma and the engineered TCR is TCR_52. In some embodiments, the solid cancer is a melanoma and the engineered TCR is TCR_73.

[0235] In some embodiments the method comprises administering a therapeutically effective amount of a composition comprising the modified lymphocytes expressing the engineered γδTCR described herein to an individual in need thereof. In some embodiments, the individual has cancer. In some embodiments, the individual has a solid cancer. V. SCREENING METHODS

[0236] In some embodiments, provided herein are methods of identifying a γδ TCR that is reactive to one or more cancer types. In some embodiments, the method comprises, a) isolating and expanding γδ T cells from one or more individuals diagnosed with cancer, each γδ T cell comprising a γδ TCR; b) culturing the γδ T cells expanded in step a) with multiple distinct cancer cell lines each comprising a cancer type, in separate wells, wherein each well contains a different cancer cell line and antibodies that bind to antigensAttorney Docket No.: 304952000240 expressed on the surface of the γδ T cells, wherein each DNA-barcode is associated with a particular cancer cell line used in the respective well; c) pooling the γδ T cells from each well of step b); d) identifying cancer reactive T cells from the pooled γδ T cells of step c); e) performing single cell sequencing on the cancer reactive γδ T cells from step d) to determine the sequence of the γδ TCR and to determine the sequence of the DNA barcode(s); and f) identifying the one or more cancer types that the γδ TCR is reactive to based upon detection of the barcode that is associated with the particular cancer cell line.

[0237] In some embodiments, isolating and expanding the γδ T cells further comprises, a) expanding the γδ T cells in an oligoclonal format; and b) selecting clonal populations of the γδ T cells that recognize cancer cells via ELISpot assay. In some embodiments, the ELISpot assay is a highly sensitive immunoassay that quantifies the number of analyte-secreting cells at high resolution.

[0238] In some embodiments, the γδ T cells are isolated from individuals diagnosed cancer. In some embodiments, the individuals are diagnosed with a solid cancer. In some embodiments, the individuals are diagnosed with breast cancer. In some embodiments, the individuals are diagnosed with renal cell carcinoma. In some embodiments, the γδ T cells are isolated from peripheral blood mononuclear cells (PBMCs) obtained from enriched leukapheresis products. In some embodiments, the γδ T cells are isolated by depleting CD11b+and CD45R+cells and enriched for γδ-TCR+cells. In some embodiments, the γδ T cells are isolated with antibody labeled magnetic particles. In some embodiments, the γδ T cells are isolated using an Anti-TCRγ / δ MicroBead Kit or an EasySep Human Gamma / Delta T Cell Isolation Kit.

[0239] In some embodiments, the culturing step b) further comprises culturing the γδ T cells in media supplemented with recombinant human IL-2 and IL-15. In some embodiments, culturing the γδ T cells in IL-2 and IL-15 activates the γδ T cells. In some embodiments, culturing the γδ T cells in IL-2 and IL-15 stimulates the γδ T cells to proliferate. In some embodiments, the γδ T cells are further activated by exposure to CD3 and CD28 agonists.

[0240] In some embodiments, the cancer cell lines in step b comprise cell lines derived from solid tumors. In some embodiments, the cancer cell lines are selected from the group consisting of Capan-2, BxPC-3, A549, SK-OV-3, OVCAR-3, HT-29, HCT116, NCI-H1975, BT-549, MDA-MB-231, and HEK293FT. In some embodiments, the cancer cells are treated with zoledronic acid before culturing with the isolated γδ T cells. In some embodiments, the cancer cell lines are further labeled with capture agents.Attorney Docket No.: 304952000240

[0241] In some embodiments, sorting the T cells based on cancer reactivity further comprises sorting the cells via flow-cytometry and gating the cells based on the expression of functional markers of T cell activation. In some embodiments, the functional markers of T cell activation are selected from the group consisting of TNFα, CD69, CD107a, and CD137. EXAMPLES

[0242] The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The attached figures are meant to be considered as integral parts of the specification and description of the disclosure. Example 1. Methods to identify, isolate, and produce T cell receptors for cancer targeting

[0243] The following example describes methods for manipulating and testing candidate T cell receptors associated with γδ T cells. Molecular cloning

[0244] TCR pairs (encompassing the TCR-γ and TCR-δ chains), identified through the single cell sequencing analysis, were codon-optimized based on preferential codon usage in Homo sapiens, separated with a self-cleaving T2A sequence and cloned using Gibson assembly into a 3rdgeneration lentiviral vector or a γ-retroviral vector as previously described (Legut, M. et al. Nature 603, 728–735 (2022). The TCRs are listed in Tables 2-5, including TCR-γ CDR amino acid sequences, (Table 2), TCR-δ CDR amino acid sequences (Table 3), TCR-γ and TCR-δ chain amino acid sequences (Table 4), and codon-optimized TCR nucleic acid sequences (Table 5). In some instances, the TCR expression was driven by the short EF-1α promoter. In some instances, the expression cassette contained a puromycin or blasticidin resistance gene downstream from TCR, separated by the self-cleaving P2A sequence. In some instances, a butyrophilin 3A1 specific (BTN3A1) TCR was used as an irrelevant TCR, as described in Gründer, C. et al. “γ9 and domains regulate functional avidity of T cells harboring γ9δ2TCRs.” Blood 120, 5153–5162 (2012), the content of which is hereinAttorney Docket No.: 304952000240 incorporated by reference in its entirety. In some instances, the viral vector contained another protein-coding gene instead of a TCR, for instance truncated NGFR, truncated EGFR, LTBR, CD80 or TNFSF9 (4-1BBL). The DNA and amino acid sequences of these protein-coding genes are listed in Table 6. Whole-plasmid sequencing (Plasmidsaurus) was used to verify the sequence of the cloned plasmids. Isolation and culture of primary human cells

[0245] Leukopaks from de-identified healthy donors and cancer patients were collected by and purchased from Stemcell. Buffy coats from de-identified healthy donors were collected by and purchased from New York Blood Center under an IRB-exempt protocol. All donors provided informed consent. Peripheral blood mononuclear cells (PBMC) were isolated from leukopaks or buffy coats using Lymphoprep™ (Stemcell) gradient centrifugation. γδ T cells were isolated from PBMC using Anti-TCRγ / δ MicroBead Kit, human (Miltenyi Biotec) or EasySep™ Human Gamma / Delta T Cell Isolation Kit (Stemcell). Immediately after isolation, T-cells were resuspended in T-cell Media, which consisted of Immunocult™-XF T-cell Expansion Medium (Stemcell) or Excellerate™ Human T cell Expansion Media (Bio- Techne) supplemented with recombinant human IL-2 and IL-15. Activation of T cells was performed with Immunocult™ Human CD3 / CD28 T-cell Activator (Stemcell), T Cell TransAct™, human (Miltenyi Biotec) Dynabeads™ CD3 / CD28 (Thermo Fisher), or direct co-culture with cancer cells. Typically, CD3+, CD4+ or CD8+ T cells were transduced with concentrated lentivirus or γ-retrovirus 24-48 hours post isolation. In certain cases, activated and virally transduced T cells were nucleofected (Lonza) with Sp. Cas9 protein (Integrated DNA Technologies (IDT)) co-complexed with an sgRNA targeting the TRBC1 and TRBC2 loci 48 hours after activation. T-cells were used for phenotypic or functional assays fresh or cryopreserved in Bambanker™ Cell Freezing Media (Bulldog Bio) or CryoStor® CS10 (Stemcell). Viral vector production

[0246] Lentiviral particles were produced by co-transfecting third-generation lentiviral transfer plasmids together with packaging plasmid psPAX2 and envelope plasmid pMD2.G into HEK293FT cells, using polyethyleneimine linear MW 25000 (Polysciences). After 72 h, the supernatants were collected, filtered through a 0.45-μm Steriflip®-HV filter (Millipore) and the virus was concentrated using Precipitation Solution (Alstem).Attorney Docket No.: 304952000240 Concentrated lentivirus was resuspended in T cell medium containing IL-2 and stored at −80°C.

[0247] γ-retroviral vectors were produced by transfection of the transfer plasmid into a packaging cell line (transient producer) or transduction into a packaging cell line (stable producer) as described before, for example in Rivière, I., Brose, K. & Mulligan, R. C. “Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells.” Proc. Natl. Acad. Sci. 92, 6733–6737 (1995) and Ghani, K. et al. “Efficient Human Hematopoietic Cell Transduction Using RD114- and GALV-Pseudotyped Retroviral Vectors Produced in Suspension and Serum-Free Media.” Hum. Gene Ther. 20, 966–974 (2009), all of which are herein incorporated by reference in their entireties. Cell culture

[0248] The following cancer cell lines were obtained from ATCC and cultured as per ATCC recommendations: Capan-2, BxPC-3, A549, SK-OV-3, OVCAR-3, HT-29, HCT116, NCI- H1975 MDA-MB-231, A375, MRC5. HEK293FT cells were obtained from Thermo Fisher Scientific and cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% Serum Plus™-II (Thermo Fisher Scientific). The cell lines were routinely tested for mycoplasma (MycoAlert™ PLUS Mycoplasma Detection Kit, Lonza) and found to be negative. In certain instances, cancer cells were pre-treated with zoledronic acid (Sigma Aldrich) for 24 hours prior to co-incubation with T cells. In some instances, cancer cells lines were nucleofected with Sp. Cas9 co-complexed with an sgRNA targeting B2M. Flow cytometry for cell surface and intracellular markers

[0249] Cells were harvested, washed with D-PBS and stained with LIVE / DEAD Violet cell viability dye for 5 minutes at room temperature in the dark, followed by surface antibody staining for 20 minutes on ice. After surface antibody staining (where applicable), the cells were washed with PBS and acquired on a flow cytometer or taken for intracellular staining. For intracellular staining, the cells were resuspended in FoxP3 / Transcription Factor Fixation Reagent (eBioscience™). After resuspension in the fixation buffer, cells were incubated at room temperature in the dark for 1 hour. Following the incubation, the cells were washed twice in the FoxP3 / Transcription Factor Permeabilization Buffer (eBioscience™). After permeabilization, the cells were stained with specific antibody or isotype control for 30Attorney Docket No.: 304952000240 minutes in the dark at room temperature. Finally, the cells were washed twice in the appropriate permeabilization buffer and acquired on a flow cytometer. Gating was performed using appropriate isotype, fluorescence minus one and biological controls. Typically, 5,000- 10,000 live events were recorded per sample.

[0250] In certain instances, T cells were cultured with cancer cells for 4-24 hours to detect activation markers. In certain instances, the T cell – cancer cell co-culture was performed in the presence of TAPI-0 (Sigma Aldrich) and antibodies against specific activation markers. ELISpot

[0251] IFNγ ELISpot was used to screen γδ T cell lines for reactivity against target cell lines. T cells were rested in T cell medium without cytokines before co-incubation with target cells. MultiScreen® 96-Well plates (EMD Millipore) were coated with mouse anti-human IFNγ capture antibody (MabTech) for 18 hours at 4⁰C. The plate was then washed with PBS and blocked with RPMI1640 supplemented with 10% fetal bovine serum for 1 hours at room temperature. After blocking, T cells (normally 50,000 per well) and target cells (normally 30,000 adherent cells) were added to the wells and incubated at 37⁰C for 18 h. The plate was then washed with PBS and incubated with ddH2O for 10 minutes, followed by one wash with PBS and addition of biotinylated anti-IFNγ antibody (Mabtech). The plate was incubated for 2 hours at room temperature and washed with PBS. Then, streptavidin-alkaline phosphatase was added to each well and incubated for 2 hours at room temperature in the dark. Finally, the plate was washed with PBS and incubated with detection reagent (Alkaline Phosphatase Conjugate Substrate Kit, Bio-Rad). After the spots developed, the reaction was stopped by washing the plate several times with tap water. TNFα / IFNγ labelling and isolation

[0252] TNFα / IFNγ-based magnetic pullout was used to enrich antigen-reactive T-cell lines, according to manufacturer’s instructions (TNFα / IFNγ Secretion Assays, Miltenyi Biotec). One day before the assay, T-cells were rested in T cell media without cytokines. The following day T-cells were co-incubated with target cells at 1:1 ratio. After 4 hours co- incubation, cells were harvested and washed two times with MACS. The cells were then re- suspended in MACS® buffer and labelled with IFNγ and TNFα Catch Reagents (all reagents from Miltenyi Biotec) for 5 minutes on ice. Catch Reagent binds to a surface marker on all leukocytes and captures IFNγ / TNFα as the are released from activated T-cells. IFNγ and TNFα capture kits were combined to maximise the number of recovered antigen-Attorney Docket No.: 304952000240 reactive cells. After labelling with the Catch Reagents, the cells were diluted in warm RPMI1640 medium supplemented with 5% fetal bovine serum and incubated at 37⁰C for 45 minutes under slow continuous rotation (cytokine secretion period). The cells were subsequently washed with MACS buffer and incubated with IFNγ / TNFα Detection Antibodies (PE-conjugated) for 10 minutes on ice. After labelling with antibodies, the cells were washed with MACS buffer and sorted on Sony MA900 cell sorter. Cell killing

[0253] Cancer cells expressing nuclear GFP were plated in a 96 flat bottom plate, with or without T cells. In some instances, T cells were sorted based on expression of activation markers in response to cancer cells. The wells were then imaged using an Incucyte® S3 with 10X magnification. For each well, the GFP object count was normalised to the first timepoint to allow the cells to fully settle after plating. Cancer cell killing was quantified by dividing the GFP object count in wells with T cells to wells with cancer cells alone. Single cell sample preparation and sequencing

[0254] For single cell sequencing, γδ T cells were co-cultured for 4-6 hours with different cancer cell lines in the presence of DNA-barcoded antibodies (TotalSeq™-C, Biolegend®). In some instances, γδ T cells were pre-selected for cancer reactivity using ELISpot. Following co-incubation, T cells were harvested, washed thoroughly, pooled and labelled with antibodies specific for activation markers or cytokine capture reagents. The labelled T cells from the cancer co-culture were then sorted for expression of activation markers or cytokines using Sony MA900 cell sorter. Sorted cancer reactive cells were then combined with control T cells (not co-cultured with cancer) which had been labelled with DNA- barcoded antibodies. The resulting cell pool was used to prepare single cell libraries using Chromium™ Single Cell V(D)J Reagent Kit (10X Genomics) with custom primers to amplify the TCR-γ and TCR-δ transcripts. The quality of produced libraries was verified on BioAnalyzer using High Sensitivity DNA kit (Agilent). The libraries were sequenced on NovaSeq™ 6000 (Illumina). Single cell sequencing analysis

[0255] Candidate TCR clonotypes were identified via a computational pipeline using both custom and published, open-source tools. The expression unique molecular identifierAttorney Docket No.: 304952000240 (UMI) count matrices were generated from the raw fastq files using 10X Genomics' CellRanger v7.2.0. HTO UMI count matrices were generated from the raw fastq files using CITE-seq-Count v1.4.5. TCR clonotypes were generated by applying the TRUST4 v.1.0.13 program to reads for each barcode separately after performing barcode correction. Gene expression data was filtered to remove empty cells and genes and to remove cells with fewer than 100 UMI counts. Additionally, cells were filtered to remove mitochondrial and ribosomal genes and to remove cells with high mitochondrial or ribosomal gene fractions. HTO data was filtered to remove empty cells and a custom adaptive filtering technique was used to call cells for each hash label. These annotations were then propagated to the other data modalities. TCR clonotypes were filtered to exclude assemblies without CDR3 annotations, and these CDR3 regions were then converted into amino acid sequences which were corrected by pooling information across the data set. Assemblies with poor-quality CDR3 annotations were then removed. TCR chains were paired and then aggregated across barcodes, forming an initial set of candidates. TCR clonotypes were then prioritized using a custom label frequency analysis that consists of calculating various frequency statistics and comparing them to empirically-generated null distributions. These null distributions were fit to appropriate theoretical distributions in order to calculate p-values for each clonotype's statistics. These p-values were then aggregated and an adjusted p-value (Bonferroni correction) with a threshold of 0.05 was used to assign significance to clonotypes, and the relative value of these adjusted p-values were used to rank candidate clonotypes. Example 2. Isolation and expansion of γδ T cells

[0256] γδ T cells from PBMCs were isolated and expanded using several methods (FIG. 1A and 1B). Following expansion, γδ T cells were co-cultured with cancer cells spanning different solid tumor indications for 4-6h and several different phenotypic and functional markers were used to detect T cells specifically recognizing cancer cells (FIG. 2A-C). In certain cases, cancer cells were pre-treated with zoledronic acid which causes accumulation of phosphorylated isoprenoid intermediates of lipid biosynthesis. T cells sorted based on the expression of phenotypic and functional markers of activation in response to cancer cells were then co-cultured again with cancer cells, showing superior cytotoxicity to unselected T cells (FIGs. 3A-3B). Having established assays enabling the selection of functional cancer- reactive γδ T cells, γδ T cells were isolated and expanded from cancer patients.Attorney Docket No.: 304952000240 Example 3. Determination of cancer specificity and reactivity

[0257] The expanded T cells were cultured with cancer cells spanning different indications in the presence of DNA-barcoded antibodies for specific enumeration of T cells responding to a given cancer indication, pooled and sorted based on cancer reactivity (FIG. 4). Alternatively, γδ T cells were expanded in a 96 well plate in an oligoclonal format and pre-selected for recognition of cancer cells using ELISpot. The wells showing an above-background frequency of cancer-reactive T cells were pooled together, co-cultured with cancer cells in the presence of DNA-barcoded antibodies and labelled with IFNγ / TNFα capture reagents for isolation of cancer-reactive T cells (FIG. 5). The sorted cancer-reactive T cells were then pooled with control T cells labelled with a separate DNA-barcoded antibody and subjected to single cell library preparation and sequencing (as described in the Methods section).

[0258] A suite of computational tools were developed that: 1) robustly reconstruct the γδ TCR sequences in each single cell; 2) enable identification of the specific condition that the T cells were exposed to, based on the DNA-barcoded antibody detection (control or specific cancer type), and 3) identify which TCRs are significantly enriched specifically in cancer- reactive T cells as compared to the control TCR clonotype distribution.

[0259] Using this method of detecting γδ TCRs with broad cancer reactivity, T cells in the single cell experiment were robustly assigned to cancer indications based on reactivity (FIG. 6A and 6B). The statistical algorithm was then applied to look for enrichment of TCRs in the cancer-reactive population over the control, specifically identifying broadly cancer-reactive γδ TCRs with cancer-specific reactivity (FIG. 7). The cancer reactivity patterns of the top identified TCRs are summarized in FIG. 8A and 8B. The TCR sequences are listed in Tables 1-6. Example 4. γδ T cell-mediated killing of various cancer types

[0260] The selected enriched TCRs were synthesized and lentivirally expressed in primary human CD3+ T cells (as described in the Methods section). The resulting TCR-transgenic T cells were then co-cultured with GFP-expressing cancer cell lines derived from different tissues. T cells engineered to express a representative TCR (Tables 2-4 TCR# 9; see Table 1 for the full sequence of the expression cassette) killed a broad range of cancer cells (FIG. 9). ConclusionsAttorney Docket No.: 304952000240

[0261] A suite of methods, spanning laboratory and computational approaches, were developed to identify TCRs with broad cancer reactivity. These TCRs may be incorporated into cell therapy products for the treatment of cancer. Table 1. DNA sequences of each of the components of the expression vector used to demonstrate the utility of a representative TCR. Component DNA Sequence SEQ nam : EFS 0 Koz 1 sequ TC 2 V se TC 3 CD TC 4 J se TC 5 C1 T2A 6 TC 7 segTCR-delta tgcgcctgcgagagcctgggcgacacctgggacaccagacagatgttcttc 958 CDR3Attorney Docket No.: 304952000240 TCR-delta J ggcaccggcatcaagctgttcgtggagccc 959 segment TC 0 seg P2A 1 Pur 2 resiExample 5. Cancer-killing capacity of donor-derived T cells engineered with γδ TCR with minimal off-target effects

[0262] 73 γδ TCRs previously identified from cancer patient T cells exhibited cytotoxic activity against multiple cancer lines. Next, the utility of these TCRs was tested by virally transducing them into healthy donor derived polyclonal T cells.

[0263] TCR-transgenic T cells were co-incubated with cancer cells from various indications to determine if the TCR itself is sufficient to direct these T cells to kill cancer cells. Robust cytotoxic activity was observed against multiple cancer cell types by ten example TCRs selected from the 73 identified TCRs (FIGs. 10A-18B). Importantly, these TCRs demonstrated capacity to kill cancer cells in the absence of zoledronic acid treatment, indicating that the targets they recognize are distinct from the well-characterized butyrophilin family as described, for example, in Hayday, et al. “Cancer immunotherapy by γδ T cells.” Science 386, eabq7248 (2024), the content of which is herein incorporated by reference in its entirety.

[0264] The existence of the above identified TCRs in cancer patients with no obvious signs of autoimmunity strongly suggests that the targets these TCRs recognize are present only on cancer cells but not broadly on healthy human cells or on human cells with other diseases. This notion was further validated by co- of TCR-engineered T cells with healthyAttorney Docket No.: 304952000240 lung fibroblasts. As shown in FIG. 19, no killing of healthy fibroblasts was observed by T cells expressing identified γδ TCRs. This result was similar to T cells engineered to recognize MAGE-A4 antigen in the context of an MHC-I allele which has undergone extensive safety testing in vitro and demonstrated no off-tumor on-target toxicities in patients as described in D’Angelo, S. P. et al. “Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.” The Lancet 403, 1460–1471 (2024), the content of which are herein incorporated by reference in its entirety.

[0265] . A HER2 CAR positive control showed reactivity to low levels of the antigen on healthy tissues, resulting in severe toxicities in the lung. As expected, the HER2 CAR but not the TCRs caused killing of healthy lung fibroblasts (FIG. 19).

[0266] To demonstrate that the activity of identified TCRs is MHC-independent, B2M was genetically knocked out in cancer cells. B2M is an essential component of all MHC-I alleles as well as similar antigen-presenting molecules that have been reported as targets for γδ TCRs: MR1, CD1a, b, c and d. Lack of B2M leads to lack of MHC-I and MR1 / CD1 molecules on cancer cells (see, e.g., Crowther, M. D. et al. “Genome-wide CRISPR–Cas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I- related protein MR1.” Nat. Immunol. 21, 178–185 (2020), the content of which is herein incorporated by reference in its entirety). The resulting loss of MHC-I and MR1 / CD1 molecules on cancer cells did not eliminate or reduce the cytotoxic activity of TCR- transduced T cells against cancer cells (FIGs. 20A-20B).

[0267] Transgenic TCR T cells typically show lower potency than CAR T cells for a variety of reasons, including lower affinity towards the antigens and lack of built-in co-stimulation. Typically, this issue is addressed by modulating the amino acid sequence of the TCR to enhance its affinity towards the cognate antigen. However, TCR affinity enhancement can result in creating new specificities which may lead to cross-reactivity with antigens expressed on healthy tissues and thus cause severe to fatal toxicities in patients, as described, for example, in Linette, G. P. et al. “Cardiovascular toxicity and titin cross-reactivity of affinity- enhanced T cells in myeloma and melanoma.” Blood 122, 863–871 (2013), the content of which are herein incorporated by reference in its entirety.

[0268] To augment potency of the TCRs without changing its primary amino acid sequence, the TCR was co-expressed with LTBR, a gene described as a positive modifier of T cell phenotype and function. See, e.g., Legut, A genome-scale screen for syntheticAttorney Docket No.: 304952000240 drivers of T cell proliferation. Nature 603, 728–735 (2022), the content of which is herein incorporated by reference in its entirety. While LTBR has been characterized extensively in the context of γδ T cells and CAR T cells, this is the first demonstration of LTBR activity in T cells expressing transgenic γδ TCRs. When co-expressed with the TCR, LTBR enabled the engineered T cells to clear cancer cells at much lower doses that T cells expressing only the TCR (FIGs. 21A-21D). Similarly, LTBR overexpression conferred increased cancer cell- killing capacity for γδ T cells expressing several different transgenic γδ TCRs against lung cancer (FIGs. 24A-24D and FIGs. 28A-28D), breast cancer (FIGs. 25A-25D), and colorectal cancer cells (FIGs. 26A-26E and FIGs. 27A-27D). This enhancement of potency was also observed by LTBR-enabled induction of secretion of a key proinflammatory cytokine, IFNγ, in response to cancer cells (FIG. 22).

[0269] Finally, as shown in FIGs. 23A-23B, CD80 and 4-1BBL co-stimulatory proteins were also demonstrated to enhance the anticancer activity of γδ TCRs. CD80 and 4-1BBL act on two main co-stimulatory pathways that have been well characterized in the context of γδ T cells (see, e.g., Park, H.-M., et al. “CD4 T-cells transduced with CD80 and 4-1BBL mRNA induce long-term CD8 T-cell responses resulting in potent antitumor effects.” Vaccine 32, 6919–6926 (2014), the content of which is herein incorporated by reference in its entirety) but their importance in the context of γδ TCRs remains poorly characterized (FIGs. 23A- 23B).

[0270] Overall, these results demonstrate that the TCRs isolated from cancer-reactive patient γδ T cells are capable of and sufficient to redirect polyclonal donor-derived T cells to kill cancer cells from various indications. This activity is MHC-I independent and cancer-specific as the TCRs remain inert to healthy cells. Further, these results show that the anticancer activity of these TCRs can be boosted by co-expression with immunosuppressive resistance genes such as LTBR or co-stimulatory proteins such as CD80 or 4-1BBL.Attorney Docket No.: 304952000240 SEQUENCES Table 2: TCR-γ chain CDR amino acid sequences. TCR-γ CDR1 TCR-γ CDR2 TCR-γ CDR3 Amino SEQ Amino Acid SEQ ID Amino Acid Se uence SEQ ID T : 1 9 29 50 52 53 54 58 61 73Table 3: TCR-δ chain CDR amino acid sequences. TC # Q NO 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 GEAIGNYY 343 EKD 344 CACVPLGDYTDKLIF 345 16 GEAIGNYY 346 EKD 347 CACDGASGGFSWDTRQMFF 348Attorney Docket No.: 304952000240 GEAIGNYY 349 EKD 350 CACDTWGMHTDKLIF 351 GEAIGNYY 352 EKD 353 CACDTVAKPPDTDKLIF 354TSWWSYY 475 QGS 476 CALGEVLRGYASPPPPFPYYTDKLIF 477 GEAIGNYY 478 EKD 479 CACDRGLHDKLIF 480Attorney Docket No.: 304952000240 61 TSWWSYY 481 QGS 482 CALGAINRHWGSLYTDKLIF 483 62 TSWWSYY 484 QGS 485 CALCSCEGNTLGGPTDKLIF 486 63 64 65 66 67 68 69 70 71 72 73Table 4. TCR-γ chain and TCR-δ chain amino acid sequences for each γδ-TCR. T TCR- chain TCR-δ chain C ASR E # Q I D N O 1 6 A 0 V 2 C K F G I R S L C 9 6 A 1 V 8 C L G L H S L C 2 6 9 E 5 V8 CATWDGHGNYKKLFGSGTTLVVTDKQLDADVSPKPTI ALGEPTPSYGRDKVKLIFGKGTRVTVEPRSQPHTKPSV FLPSIAETKLQKAGTYLCLLEKFFPDVIKIHWQEKKSNT FVMKNGTNVACLVKEFYPKDIRINLVSSKKITEFDPAIAttorney Docket No.: 304952000240 ILGSQEGNTMKTNDTYMKFSWLTVPEKSLDKEHRCIV VISPSGKYNAVKLGKYEDSNSVTCSVQHDNKTVHSTD RHENNKNGVDQEIIFPPIKTDVITMDPKDNCSKDANDT FEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHTEK LLLQLTNTSAYYMYLLLLLKSVVYFAIITCCLLRRTAF VNMMSLTVLGLRMLFAKTVAVNFLLTAKLFFL C M 7 E 0 V 0 C P L T L H I L C M 7 I 0 V 4 A P A T Q N I Q G M 7 E 0 D 6 Y V F I D R L C M 7 I 0 V 8 A V T N D I D A M 7 E 1 V 6 C H P G HLLQLTNTSAYYMYLLLLLKSVVYFAIITCCLLRRTAFC VHTEKVNMMSLTVLGLRMLFAKTVAVNFLLTAKLFF CNGEKS LAttorney Docket No.: 304952000240 6 MQWALAVLLAFLSPASQKSSNLEGRTKSVIRQTGSSA 7 MLFSSLLCVFVAFSYSGSSVAQKVTQAQSSVSMPVRK 7 1 EITCDLAEGSTGYIHWYLHQEGKAPQRLLYYDSYTSS 2 AVTLNCLYETSWWSYYIFWYKQLPSKEMIFLIRQGSD 2 VVLESGISPGKYDTYGSTRKNLRMILRNLIENDSGVYY 1 EQNAKSGRYSVNFKKAAKSVALTISALQLEDSAKYFC 2 C S F I R L C 7 7 3 A 4 V 6 C P I T V T FTable 5. Codon optimized TCR nucleic acid sequences TCRSEQ ID NO 1 802CCAACGACACCTACATGAAGTTCAGCTGGC GAGAACACCAAGCAGCCCAGCAAGTCCTGCCACA TGACCGTGCCTGAGAAGTCCCTGGACAAA AGCCTAAGGCCATCGTGCACACCGAGAAAGTGAAAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 9 818 29 858AACCTGGAAGGCAGGACCAAGAGCGTGAT GTGACACAGGCCCAGTCCTCCGTGTCTATGCCTGT CAGACAGACAGGATCCAGCGCCGAGATCA GCGGAAAGCCGTGACACTGAACTGCCTGTACGAGAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 50 900TGCAGAAGGCCGGCACCTATCTGTGCCTGC TCTAGCAAGAAGATCACCGAGTTCGACCCCGCCA TGGAAAAGTTCTTCCCAGACGTGATCAAGA TCGTGATCAGCCCTAGCGGCAAGTACAACGCCGTAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 52 904CCATCATCACCTGTTGCCTGCTGCGGAGAA CCGCCTTCTGCTGCAATGGCGAGAAATCTAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 53 906 54 908ACCCCAGAAACTACTACAAGAAGCTGTTC GAACCTAGAAGCCAGCCTCACACCAAGCCTAGCG GGCAGCGGCACCACCCTGGTGGTGACCGA TGTTCGTGATGAAGAACGGCACCAACGTGGCCTGAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 58 916AAGGACGCCAACGATACCCTGCTGCTGCA CCTG GCTGACAAACACCAGCGCCTACTACATGTAAttorney Docket No.: 304952000240TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NO 61 922 73 946TGGTGTCCATCAGCTACGATGGCACCGTGC GGCAGATACAGCGTGAACTTCAAGAAAGCCGCCA GGAAAGAGAGCGGCATCCCTTCTGGCAAG AGTCTGTGGCCCTGACCATCTCTGCTCTGCAGCTGAttorney Docket No.: 304952000240 TCR #TCR-γ chain TCR-δ chain Nucleic acid Sequence SEQ Nucleic acid Sequence SEQ ID NOTable 6. DNA and amino acid sequences of proteins used to demonstrate the utility of a representative TCR Co Q nam : Irre 3 TC (BT spec nuc sequCCCTAAGCCTACCATCTTCCTGCCTTCTATCGCCGAGACAAAGCTGCAGAAAttorney Docket No.: 304952000240 GATCCACTGGCAAGAGAAGAAGTCCAACACCATCCTGGGCAGCCAAGAGG GCAACACCATGAAGACCAACGACACCTACATGAAGTTCAGCTGGCTGACC Irre 4 TC (BT spec ami sequNSVTCSVQHDNKTVHSTDFEVKTDSTDHVKPKETENTKQPSKSCHKPKAIVHT EKVNMMSLTVLGLRMLFAKTVAVNFLLTAKLFFLAttorney Docket No.: 304952000240 MAGE-A4 ATGAAGAAGCACCTGACCACCTTTCTGGTCATCCTGTGGCTGTACTTCTAC 965 TCR AGAGGCAACGGCAAGAACCAGGTGGAACAGAGCCCTCAGAGCCTGATCA nuc sequ MA 6TCR amino LRWYKQDTGRGPVSLTILTFSENTKSNGRYTATLDADTKQSSLHITASQLSDS acid sequenceAttorney Docket No.: 304952000240 LFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACA NAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAG Tru 7 NG nuc sequ Tru 8 NG acid Tru 9 EG nuc sequtccaacgaatgggcctaagatcccgtccatcgccactgggatggtgggggccctcctcttgctgctggtggtggccctggg gatcggcctcttcatgAttorney Docket No.: 304952000240 Truncated MLLLVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSIS 970 EGFR amino GDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF acid LTB 1 nuc sequ LTB 2 acidKDEVGKGNNHCVPCKAGHFQNTSSPSARCQPHTRCENQGLVEAAPGTAQSDAttorney Docket No.: 304952000240 LLKRRPQGEGPNPVAGSWEPPKAHPYFPDLVQPLLPISGDVSPVSTGLPAAPV LEAGVPQQQSPLDLTREPQLEPGEQSQVAHGTNGIHVTGGSMTITGNIYIYNG CD 3 nuc sequ CD 4 acid 4-1 5 nuc sequ 4-1 6 ami sequAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE

Claims

Attorney Docket No.: 304952000240 Claims 1. A modified lymphocyte comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR further comprises: a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 601, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 602; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 617, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 618; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 657, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 658; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 699, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 700; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 703, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 704; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO: 705, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 706; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:707, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 708;Attorney Docket No.: 304952000240 a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:715, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:716; a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:721, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO: 722; or a CDR1, a CDR2, and a CDR3 of the TCR-γ chain comprising the amino acid sequence set forth in SEQ ID NO:745, and a CDR1, a CDR2, and a CDR3 of the TCR-δ chain comprising the amino acid sequence set forth in SEQ ID NO:

746.

2. The modified lymphocyte of claim 1, wherein the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:301, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:302, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:303; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:27, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:325, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:326, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:327; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:85, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:86, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:87, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:385, a CDR2 amino acid sequence set forth in SEQ IDAttorney Docket No.: 304952000240 NO:386, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:387; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:148, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:149, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:150, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:448, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:449, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:450; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:454, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:455, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:456; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:457, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:458, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:459; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:460, a CDR2 comprising amino acid sequence set forth in SEQ IDAttorney Docket No.: 304952000240 NO:461, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:462; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:472, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:473, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:474; the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:183, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:481, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:482, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:482; or the TCR-γ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:217, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:218, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:219, and wherein the TCR-δ extracellular antigen binding domain comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO:517, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO:518, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO:

519.

3. The modified lymphocyte of claim 1 or claim 2, wherein the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:601, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:602; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:617, and the TCR-δ chain comprises the amino sequence set forth in SEQ ID NO:618;Attorney Docket No.: 304952000240 the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:657, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:658; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:699, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:700; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:703, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:704; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:705, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:706; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:707, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:708; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:715, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:716; the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:721, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:722; or the TCR-γ chain comprises the amino acid sequence set forth in SEQ ID NO:745, and the TCR-δ chain comprises the amino acid sequence set forth in SEQ ID NO:

746.

4. The modified lymphocyte of any one of claims 1-3, wherein the TCR comprises a Vδ1+ chain, a Vδ2+chain, or a Vδ3+ chain.

5. The modified lymphocyte of any one of claims 1-4, wherein the TCR is a Vγ9Vδ2 gamma-delta TCR.

6. The modified lymphocyte of any one of claims 1-5, wherein the TCR comprise a Vγ9 chain.

7. The modified lymphocyte of any one of claims 1-6, wherein the TCR is a non- Vγ9Vδ2 gamma-delta TCR.

8. The modified lymphocyte of any one of claims 1-7, wherein the transmembrane domain comprises an amino acid sequence set forth in SEQ ID NOs:551-552.

9. The modified lymphocyte of any one of claims 1-8, wherein the TCR-γ chain comprises a transmembrane domain amino acid sequence set forth in SEQ ID NO:551.Attorney Docket No.: 304952000240 10. The modified lymphocyte of any one of claims 1-8, wherein the TCR-δ chain comprises a transmembrane domain comprising the amino acid sequence set forth in SEQ ID NO:

552.

11. The modified lymphocyte of any one of claims 1-10, wherein the intracellular domain comprises an amino acid sequence set forth in SEQ ID NOs:561-562.

12. The modified lymphocyte of any one of claims 1-11, wherein the TCR-γ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:

561.

13. The modified lymphocyte of any one of claims 1-11, wherein the TCR-δ chain comprises an intracellular domain comprising the amino acid sequence set forth in SEQ ID NO:

562.

14. The modified lymphocyte of any one of claims 1-13, wherein the modified lymphocyte is a CD3+ T cell.

15. The modified lymphocyte of any one of claims 1-14, wherein the modified lymphocyte is a CD4+ T cell or a CD8+ T cell.

16. The modified lymphocyte of any one of claims 1-14, wherein the modified lymphocyte is a gamma-delta T cell.

17. The modified lymphocyte of any one of claims 1-16, wherein the modified lymphocyte is a primary human lymphocyte.

18. The modified lymphocyte of any one of claims 1-17, wherein the modified lymphocyte is an autologous lymphocyte.

19. The modified lymphocyte of any one of claims 1-18, wherein the modified lymphocyte is reactive toward a single cancer cell type.

20. The modified lymphocyte of any one of claims 1-18, wherein the modified lymphocyte is reactive toward more than one cancer cell type.

21. The modified lymphocyte of any one of claims 20, wherein the modified lymphocyte is reactive toward two, three, four, or five cancer cell types.Attorney Docket No.: 304952000240 22. The modified lymphocyte of any one of claims 1-21, wherein the modified lymphocyte comprises enhanced cytotoxicity towards a cancer cell type compared to the cytotoxicity of an unmodified lymphocyte to the same cancer cell type.

23. The modified lymphocyte of any one of claims 1-22, wherein the modified lymphocyte comprises an immunosuppressive resistance gene that enhances cytotoxicity towards a cancer cell type compared to the cytotoxicity of a lymphocyte that does not comprise the immunosuppressive resistance gene to the same cancer cell type.

24. The modified lymphocyte of claim 23, wherein the immunosuppressive resistance gene is LTBR.

25. The modified lymphocyte of any one of claims 1-24, further comprising a co- stimulatory protein or functional portion thereof that enhances cytotoxicity towards a cancer cell type compared to the cytotoxicity of a lymphocyte that does not comprise the co- stimulatory protein or functional portion thereof to the same cancer cell type.

26. The modified lymphocyte of claim 25, wherein the co-stimulatory protein or functional portion thereof is CD80 or 4-1BBL.

27. The modified lymphocyte of any one of claims 1-26, wherein the cancer cell type is selected from the group consisting of lung, breast, pancreatic, melanoma, colorectal, and ovarian cancer.

28. The modified lymphocyte of any one of claims 1-27, wherein the exogenous nucleic acid comprises an expression cassette comprising a promoter that is operably linked to the nucleic acid encoding the TCR.

29. The modified lymphocyte of claim 28, wherein the promoter is selected from the group consisting of cytomegalovirus (CMV) immediate-early enhancer, chicken beta-actin (CAG), human beta-actin, elongation factor 1α (EF1α), SV40, ubiquitin C (UbC), tetracycline response element (TRE), and PGK.

30. The modified lymphocyte of claim 28 or claim 29, wherein the promoter is a short EF-1α promoter.

31. The modified lymphocyte of any one of claims 28-30, wherein the promoter is a ubiquitous promoter.Attorney Docket No.: 304952000240 32. The modified lymphocyte of any one of claims 28-31, wherein the promoter drives constitutive expression of the TCR.

33. The modified lymphocyte of any one of claims 28-32, wherein the promoter is an inducible promoter.

34. The modified lymphocyte of any one of claims 28-33, wherein the expression cassette further comprises a puromycin or blasticidin resistance gene.

35. The modified lymphocyte of any one of claims 28-34, wherein the expression cassette further comprises polynucleotides encoding an intracellular enzyme, an immunosuppressive resistance gene, a fluorescent protein, and / or a surface expressed safety switch protein.

36. The modified lymphocyte of claim 35, wherein the immunosuppressive resistance gene is LTBR.

37. The modified lymphocyte of claim 35 or claim 36, wherein the surface expressed safety switch protein comprises full length CD20, HER2, EGFR, and / or NGFR, or a functional fragment thereof.

38. The modified lymphocyte of any one of claims 28-37, wherein the expression cassette is integrated into the genome of the modified lymphocyte.

39. The modified lymphocyte of any one of claims 28-38, wherein the expression cassette is integrated into a native TCR genomic locus of the modified lymphocyte.

40. The modified lymphocyte of any one of claims 28-39, wherein the expression cassette is integrated into a safe harbor locus of the modified lymphocyte.

41. The modified lymphocyte of any one of claims 28-38, wherein the expression cassette is randomly integrated into the genome of the modified lymphocyte.

42. The modified lymphocyte of any one of claims 28-41, wherein the nucleic acid encoding the TCR comprises a codon-optimized nucleic acid sequence set forth in SEQ ID NOs:801-946.

43. A vector encoding an engineered TCR comprising a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 4, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 4.Attorney Docket No.: 304952000240 44. The vector of claim 43, wherein the vector is a viral vector.

45. The vector of claim 43 or claim 44, wherein the vector is a lentivirus, an adenovirus, a retrovirus, or a baculovirus.

46. The vector of claim 45, wherein the vector is an episomal or non-integrating vector.

47. The vector of claim 46, wherein the episomal vector is a Simian virus 40 (SV40), Adenovirus, or Adeno-associated vector.

48. The vector of claim 43, wherein the vector is a non-viral vector.

49. The vector of claim 48, wherein the non-viral vector is a plasmid.

50. The vector of claim 48 or claim 49, wherein the non-viral vector is delivered to a lymphocyte by electroporation or cell squeezing.

51. The vector of any one of claims 48-50, wherein the non-viral vector is encapsulated in nanoparticles or liposomes.

52. A method of killing cancer cells in an individual comprising providing to the individual a population of the modified lymphocyte as defined in any one of claims 1-42.

53. The method of claim 52, wherein the cancer cells are selected from the group consisting of ovarian cancer cells, breast cancer cells, lung cancer cells, pancreatic cancer cells, colorectal cancer cells, and melanoma cancer cells.

54. A method of treating cancer in an individual comprising providing to the individual a population of the modified lymphocyte as defined in any one of claims 1-42.

55. The method of claim 54, wherein the cancer is a solid cancer.

56. The method of claim 55, wherein the solid cancer is an epithelial cancer or a melanoma.

57. The method of claim 56, wherein the epithelial cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer.

58. A composition comprising the modified lymphocyte as defined in any one of claims 1-42.Attorney Docket No.: 304952000240 59. A method of identifying a γδ TCR that is reactive to one or more cancer types, the method comprising: a) isolating and expanding γδ T cells from one or more individuals diagnosed with cancer, each γδ T cell comprising a γδ TCR; b) culturing the γδ T cells expanded in step a) with multiple distinct cancer cell lines each comprising a cancer type, in separate wells, wherein each well contains a different cancer cell line and DNA-barcoded antibodies that bind to antigens expressed on the surface of the γδ T cells, wherein each DNA-barcode is associated with a particular cancer cell line used in the respective well; c) pooling the γδ T cells from each well of step b); d) identifying cancer reactive T cells from the pooled γδ T cells of step c); e) performing single cell sequencing on the cancer reactive γδ T cells from step d) to determine the sequence of the γδ TCR and to determine the sequence of the DNA barcode(s); and f) identifying the one or more cancer types that the γδ TCR is reactive to based upon detection of the barcode that is associated with the particular cancer cell line.

60. The method of claim 59, wherein the isolating and expanding the γδ T cells comprises a) expanding the γδ T cells in an oligoclonal format; and b) selecting clonal populations of the γδ T cells that recognize cancer cells via ELISpot assay.

61. The method of claim 59 or claim 60, wherein the γδ T cells are isolated from individuals diagnosed with cancers selected the group consisting of breast cancer and renal cell carcinoma.

62. The method of any one of claims 59-61, wherein the γδ T cells are isolated from peripheral blood mononuclear cells (PBMCs) obtained from enriched leukapheresis products.

63. The method of any one of claims 59-62, wherein the γδ T cells are isolated using a human Anti-TCRγ / δ MicroBead Kit or an EasySep Human Gamma / Delta T Cell Isolation Kit.

64. The method of any one of claims 59-63, wherein the isolated T cells are cultured in T- cell media supplemented with recombinant human IL-2 and IL-15.Attorney Docket No.: 304952000240 65. The method of any one of claims 59-64, wherein the isolated T cells are further activated by exposure to CD3 and CD28 agonists.

66. The method of any one of claims 59-65, wherein the cancer cell lines are derived from solid tumors.

67. The method of any one of claims 59-66, wherein the cancer cells are selected from the group consisting of Capan-2, BxPC-3, A549, SK-OV-3, OVCAR-3, HT-29, HCT116, NCI- H1975, BT-549, MDA-MB-231, and HEK293FT.

68. The method of any one of claims 59-67, wherein the cancer cell lines are treated with zoledronic acid before culturing with the isolated γδ T cells.

69. The method of any one of claims 59-68, wherein the cancer cell lines are further labeled with IFNγ / TNFα capture agents.

70. The method of any one of claims 59-69, wherein sorting the T cells based on cancer reactivity further comprises sorting the cells via flow-cytometry and gating the cells based on the expression of functional markers of T cell activation.

71. The method of claim 70, wherein the functional markers of T cell activation are selected from the group consisting of TNFα, CD69, CD107a, and CD137.

72. A gamma-delta TCR comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the gamma-delta TCR comprises a CDR1, a CDR2, and a CDR3 of a TCR-γ chain comprising an amino acid sequence set forth in Table 4, and a CDR1, a CDR2, and a CDR3 of a TCR-δ chain comprising an amino acid sequence set forth in Table 4.

73. A method of treating cancer in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. wherein the modified lymphocyte is cancer reactive, wherein the cancer is a solid cancer.Attorney Docket No.: 304952000240 74. A method of killing cancer cells in an individual comprising providing to the individual a population of modified lymphocytes comprising an exogenous nucleic acid encoding an engineered T cell receptor (TCR) comprising a TCR-γ chain and a TCR-δ chain, wherein the TCR-γ chain and the TCR-δ chain each comprise an extracellular antigen binding domain, a transmembrane domain, and an intracellular domain, wherein the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73. wherein the modified lymphocyte is cancer reactive, wherein the cancer cells are derived from a solid cancer.

75. The method of claim 73 or claim 74, wherein the solid cancer is an epithelial cancer or a melanoma.

76. The method of claim 75, wherein the epithelial cancer is selected from the group consisting of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, and colorectal cancer.

77. The method of claim 75 or claim 76, wherein the solid cancer is an epithelial cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_50, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73.

78. The method of any one of claims 75-77, wherein the epithelial cancer is ovarian cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_29, TCR_52, TCR_53, TCR_54, TCR_58, TCR_61, and TCR_73.

79. The method of any one of claims 75-77, wherein the epithelial cancer is breast cancer and the engineered TCR is selected from the group consisting of TCR_09, TCR_29, TCR_50, TCR_52, TCR_61, and TCR_73.

80. The method of any one of claims 75-77, wherein the epithelial cancer is lung cancer and the engineered TCR is selected from the group consisting of TCR_01, TCR_09, TCR_52, TCR_53, TCR_54, TCR_61, and TCR_73.

81. The method of any one of claims 75-77, wherein the epithelial cancer is pancreatic cancer and the engineered TCR is TCR_09.

82. The method of any one of claims 75-77, wherein the epithelial cancer is colorectal cancer and the engineered TCR is selected from the group consisting of TCR_09, TCR_29, TCR_50, TCR_52, TCR_61, and TCR_73.Attorney Docket No.: 304952000240 83. The method of claim 75, wherein the solid cancer is a melanoma and the engineered TCR is selected from the group consisting of TCR_29, TCR_50, TCR_52, and TCR_73.