Antibodies targeted to osteopontin and uses thereof for reducing resistance of solid tumors immune cell therapy

Abstract

Described herein are methods and compositions for treating patients suffering from a cancer by administering antibodies targeted to osteopontin (OPN or SPP1) and a population of immune cells expressing a chimeric antigen receptor (CAR). Also included are methods of improving the efficacy of immune cell therapy using CARs (e.g., CAR T cells) by administering antibodies targeted to SPP1.

Description

[0001]Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Antibodies Targeted to Osteopontin and Uses Thereof for Reducing Resistance of Solid Tumors Immune Cell Therapy CLAIM OF PRIORITY This application claims the benefit of U.S. Provisional Application Serial No.63 / 644,467, filed on May 8, 2024. The entire contents of the foregoing are incorporated herein by reference. TECHNICAL FIELD This disclosure relates to novel antibodies targeted to osteopontin (OPN or SPP1) as well as immune cell therapy methods using chimeric antigen receptors (CAR) and antibodies targeted to SPP1. BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has exhibited notable success in treating certain lymphomas, some forms of leukemia, and multiple myeloma. However, CAR T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment (TME), characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy and there is a need for therapies that reduce resistance to immune cell therapies, e.g., CAR T cell therapy. SUMMARY Described herein, inter alia, are methods for improving the efficacy of CAR T cells by administering antibodies targeted to osteopontin (OPN or SPP1). Also described herein are novel antibodies targeted to SPP1 (also called SPP-1 throughout) and use of these antibodies. Glioblastoma stands out as a highly lethal solid tumor, displaying restricted response to conventional as well as emerging treatments. The response to immunotherapies in solid tumors is intricately determined by the dynamic interplay of components within the tumor microenvironment (TME), underscoring an augmented immune response in an inflammatory milieu with activated immune cells. Notably, the anti-tumor effects of CAR T cell therapies are manifested not only through tumor-directed cytotoxicity, but also through the more pronounced and indirect modulation of the endogenous immune system against malignant cells. In a recently reported phase 1 clinical trial evaluating IL13Ra2-targeted CAR T cells in recurrentAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017high-grade gliomas, our investigation revealed heterogenous therapeutic responses with improved outcomes for patients whose pre-treatment tumors exhibited higher infiltration of endogenous CD3 cells and increased levels of IFNg-pathway cytokines during treatment. While half of the patients achieved stable disease or better, half of the patients progressed through treatment, thereby highlighting challenges that remain for addressing resistance observed in most gliomas largely marked by inherent heterogeneity in intercellular networks and the prevalence of suppressive programs predominantly governed by abundant heterogeneous macrophages—an aspect yet to be fully understood. As described in greater detail below, we used an analytically intensive approach to decipher the suppressive network within these tumors in the studies presented in this application. This involved not only utilizing scRNA seq of pretreatment tumors undergoing CAR T cell therapy, but also investigating tumor models that faithfully replicate this specific immune landscape. We utilized IFN deficient models, functionally verified for their lack of response to checkpoint blockade therapies due to dominant mechanisms such as the absence of antigen presentation and inactivation of T cell recognition. Despite the MHC-independent mechanism of action of CAR T cells, our findings reveal a significant deficiency in response in this model, driven strongly by a suppressive network of immune components that hampers CAR T cell endurance and activation within the tumor. Building upon this insight, our subsequent integrative analysis of these distant tumors highlighted similarities and unveiled the dominant role of SPP1 expressing macrophages that govern resistance networks to CAR T cell therapies. Importantly, SPP1 blockade reversed tumor resistance and strongly enhanced CAR T cell therapy. These findings underscore the significance of a primed, receptive TME for optimal CAR T cell efficacy and highlights the dominant suppressive role of SPP1+ macrophages in abrogating CAR T cell therapeutic response. In some embodiments, an SPP1 antibody can be used together with a CAR targeted to, for example, human IL13Ra2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA. Importantly, the SPP1 antibody is preferably administered prior to administration of the CAR. Thus, in some embodiments, the administration of the SSP1 antibody can precede administration of the CAR by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or longer. In some embodiments, the SPP1 antibody is administered several times prior to the administration of the CAR and the second or subsequent administration of the SPP1 antibody can be at any point prior to, coincident with, or subsequent to administration of the CAR.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Thus, described herein, inter alia, are methods of treating cancer (e.g., solid tumors). The cancer being treated, for example glioblastoma, can be characterized by infiltration with macrophages with elevated expression of SPP1. In some embodiments, the cancer being treated is a glioma. In some embodiments, the cancer being treated is a solid tumor. In some embodiments, the cancer being treated is a solid tumor that comprises cells that express IL13Ra2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA, including metastases thereof. Methods for treating a human patient suffering from a cancerous solid tumor can comprise: (a) administering to the patient an antibody targeted to osteopontin (SPP-1); and (b) subsequently administering to the human patient a population of immune cells expressing a chimeric antigen receptor (CAR) targeted to a solid tumor antigen. In some embodiments, methods of treating a patient suffering from a cancer (e.g., a cancer comprising cells with elevated SPP1 expression and / or a cancer comprising cells expressing IL13Ra2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA) comprise first administering an SPP1 antibody followed by administering a population of immune cells expressing a CAR (e.g., a IL-13 CAR, CLTX CAR, EGFR CAR, TAG72 CAR, B7H3 CAR, CD70 CAR, HER2 CAR, PSCA CAR, or PSMA CAR); and optionally wherein the SPP1 antibody is administered to the patient before the population of immune cells expressing the CAR. SPP1 Antibody Described herein, inter alia, are SPP1 antibodies and methods of use. A variety of antibodies targeted to SPP1 are useful in the methods of the invention. For example, US 2021 / 0188959 describes four different SPP-1 antibodies that bind to mouse OPN: 1) Clone 100G2-2 comprising a VL domain comprising or consisting of: MKLPVRLLVLMFWIPASNSDVVMTQTPLSLPVRLGDQASISCRPSQSIVHGNRKTYLE WYLQKPGQSPKWYKVSNRFSGVPDRFSGSRSGTDFTLKISRVEAADLGVYYCFQGSH VPWTFGGGTKLEIK (SEQ ID NO:61 with the signal sequence (underlined); SEQ ID NO: 62 without the signal sequence) and having CDR1: RPSQSIVHGNRKTYLE (SEQ ID NO: 63); CDR2: KVSNRFS (SEQ ID NO:64); and CDR3: FQGSHVPWT (SEQ ID NO: 65); and a VH domain comprising or consisting of MEWSWVFLFLLSVIAGVQSQVHLQQSGADLVRPGASVTLSCKASGYTFTDFEMHWVK QTPVHGLDWIGAIDPETGSTGYNQKFKDKAILTADRSSSTAYMELRSLTSEDSAVYYAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017CARAYYNNYRDYAMDYWGQGTSVAVSS (SEQ ID NO:66 with the signal sequence (underlined); SEQ ID NO: 67 without the signal sequence) and having CDR1: DFEMEI (SEQ ID NO:68; CDR2: AIDPETGSTGYNQKFKD (SEQ ID NO: 69); and CDR3: AYYNNYRDYAMDY (SEQ ID NO:70). 2) Clone 100D3-2 comprising a VL domain comprising or consisting of: MSPAQFLILLVLWIRETNGDVVMTQTPLTLSVTIGRPASISCKSSQSLLESDGKTYLNWL LQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFP RTFGGGTKLEIK (SEQ ID NO:71 with the signal sequence (underlined); SEQ ID NO: 72 without the signal sequence) and having CDR1: KSSQSLLESDGKTYLN (SEQ ID NO:73); CDR2 LVSKLDS (SEQ ID NO:74); and CDR3 WQGTHFPRT (SEQ ID NO:75); and a VH domain comprising or consisting of: MGWSCIMLFLAATATGVHSQVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWV KQRPGRGLEWIGRIVPKSGDTKYNEKFKSKATLTVDKPSSTAYMQLSSLTSEDSAV YYCARESGYWGQGTTLTVSS (SEQ ID NO:76 with the signal sequence (underlined); SEQ ID NO: 77 without the signal sequence) and having CDR1: SYWMH (SEQ ID NO:78); CDR2: RIVPKSGDTKYNEKFKS (SEQ ID NO:79); and CDR3 ESGY (SEQ ID NO:80). 3) Clone 103D6-1 comprising a VL domain comprising or consisting of: MRFSAQLLGLLVLWIPGSTAEIVMTQAAFSKPVTLGTSASISCRSSKSLLQRNGITYLC WFLQRPGQSPQLLIYQMSNLASGVPDRFSCSGSGTEFTLRISRVEAEDVGVYYCAQDLE LPPTFGGGTKLEIR (SEQ ID NO:81 with the signal sequence (underlined); SEQ ID NO: 82 without the signal sequence) and having CDR1 RSSKSLLQRNGITYL (SEQ ID NO:83); CDR2: QMSNLAS (SEQ ID NO:84); and CDR3: AQDLELPPT (SEQ ID NO:85); and a VH domain comprising or consisting of MDSRLNLVFLVLILKGVQCEVQLVESGGGLVKPGGSLKLSCAASGFTFSDYGMHFVRQ APERGLEWVAYINSRSDTIYYVDTVKGRFTISRDNAKNTLFLQMTSLRSEDTAIYYCAR EYYGMDYWGQGTSVTVSS (SEQ ID NO:86 with the signal sequence (underlined); SEQ ID NO: 87 without the signal sequence) and having CDR1: DYGH (SEQ ID NO:88); CDR2 YINSRSDTIYYVDTVKG (SEQ ID NO:89); and CDR3: EYYGMDY (SEQ ID NO:90). 4) Clone 89G9-1 comprising a VL domain comprising or consisting of: MRFSAQLLGLLVLWIPGSTADIVMTQAAFSNPVTLGTSASISCRSSKSLLHTNGITYLY WFLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLRISRVEAEDVGVYYCAQNLE LPPTFGGGTKLEIK (SEQ ID NO:91 with the signal sequence (underlined); SEQ ID NO: 92 without the signal sequence) and having CDR1: RSSKSLLHTNGITYLY (SEQ ID NO:93); CDR2: QMSNLAS (SEQ ID NO: 94); and CDR3: AQNLELPPT (SEQ ID NO:95); and a VHAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017domain comprising or consisting of: MDSRLNLVFLVLILKGVQCEVQLVESGGGLVKPGGSLKLSCVVSGFTFNNYEMHWVRL APEKGLEWIAYINSGSRTIYYADTVKGRFTISRDNAKNILFLQMTNLRSEDTAMYYCTR YYHAMDYWGQGTSVTVSS (SEQ ID NO:96 with the signal sequence (underlined); SEQ ID NO: 97 without the signal sequence) and having CDR1: NYEMH (SEQ ID NO:98); CDR2: YINSGSRTIYYADTVKG (SEQ ID NO:99); and CDR3: YYHAMDY (SEQ ID NO: 100). In some embodiments, the antibody targeted to SPP1 comprises: (a) a light chain domain (LC) comprising a variable light (VL) chain domain comprising of any one of: i. CDR1 comprising or consisting of SEQ ID NO: 63; CDR2 comprising or consisting of SEQ ID NO:64; and CDR3 comprising or consisting of SEQ ID NO: 65; ii. CDR1 comprising or consisting of SEQ ID NO:73; CDR2 comprising or consisting of SEQ ID NO:74; and CDR3 comprising or consisting of SEQ ID NO:75; iii. CDR1 comprising or consisting of SEQ ID NO:83; CDR2 comprising or consisting of SEQ ID NO:84; and CDR3 comprising or consisting of SEQ ID NO:85; iv. CDR1 comprising or consisting of SEQ ID NO:93; CDR2 comprising or consisting of SEQ ID NO: 94; and CDR3 comprising or consisting of SEQ ID NO:95; v. CDR1 comprising or consisting of SEQ ID NO:P2; CDR2 comprising or consisting of SEQ ID NO:P3; and CDR3 comprising or consisting of SEQ ID NO:P4; vi. CDR1 comprising or consisting of SEQ ID NO:P10; CDR2 comprising or consisting of SEQ ID NO: P11; and CDR3 comprising or consisting of SEQ ID NO: P12); vii. CDR1 comprising or consisting of SEQ ID NO:P18; CDR2 comprising or consisting of SEQ ID NO: P19; and CDR3 comprising or consisting of SEQ ID NO: P20); viii. CDR1 comprising or consisting of SEQ ID NO:P26; CDR2 comprising or consisting of SEQ ID NO: P27; and CDR3 comprising or consisting of SEQ ID NO:P28);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017ix. CDR1 comprising or consisting of SEQ ID NO:P34; CDR2 comprising or consisting of SEQ ID NO: P35; and CDR3 comprising or consisting of SEQ ID NO: P36); x. CDR1 comprising or consisting of SEQ ID NO:P42; CDR2 comprising or consisting of SEQ ID NO: P43; and CDR3 comprising or consisting of SEQ ID NO:P44); xi. CDR1 comprising or consisting of SEQ ID NO:P50; CDR2 comprising or consisting of SEQ ID NO: P51; and CDR3 comprising or consisting of SEQ ID NO:P52); xii. CDR1 comprising or consisting of SEQ ID NO:P58; CDR2 comprising or consisting of SEQ ID NO: P59; and CDR3 comprising or consisting of SEQ ID NO:P60); xiii. CDR1 comprising or consisting of SEQ ID NO:P66; CDR2 comprising or consisting of SEQ ID NO: P67; and CDR3 comprising or consisting of SEQ ID NO:P68); xiv. CDR1 comprising or consisting of SEQ ID NO:P74; CDR2 comprising or consisting of SEQ ID NO:P75; and CDR3 comprising or consisting of SEQ ID NO:P76); xv. CDR1 comprising or consisting of SEQ ID NO:P82; CDR2 comprising or consisting of SEQ ID NO: P83; and CDR3 comprising or consisting of SEQ ID NO:P84); xvi. CDR1 comprising or consisting of SEQ ID NO:P90; CDR2 comprising or consisting of SEQ ID NO: P91; and CDR3 comprising or consisting of SEQ ID NO:P92); xvii. CDR1 comprising or consisting of SEQ ID NO:P98; CDR2 comprising or consisting of SEQ ID NO: P99; and CDR3 comprising or consisting of SEQ ID NO:P100); xviii. CDR1 comprising or consisting of SEQ ID NO:P106; CDR2 comprising or consisting of SEQ ID NO: P107; and CDR3 comprising or consisting of SEQ ID NO:P108); xix. CDR1 comprising or consisting of SEQ ID NO:P114; CDR2 comprising or consisting of SEQ ID NO: P115; and CDR3 comprising or consisting of SEQ ID NO:P116);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xx. CDR1 comprising or consisting of SEQ ID NO:P122; CDR2 comprising or consisting of SEQ ID NO: P123; and CDR3 comprising or consisting of SEQ ID NO: P124); xxi. CDR1 comprising or consisting of SEQ ID NO:P130; CDR2 comprising or consisting of SEQ ID NO: P131; and CDR3 comprising or consisting of SEQ ID NO:P132); xxii. CDR1 comprising or consisting of SEQ ID NO:P138; CDR2 comprising or consisting of SEQ ID NO: P139; and CDR3 comprising or consisting of SEQ ID NO:P140); xxiii. CDR1 comprising or consisting of SEQ ID NO:P146; CDR2 comprising or consisting of SEQ ID NO: P147; and CDR3 comprising or consisting of SEQ ID NO:P148); xxiv. CDR1 comprising or consisting of SEQ ID NO:P154; CDR2 comprising or consisting of SEQ ID NO: P155; and CDR3 comprising or consisting of SEQ ID NO:P156); xxv. CDR1 comprising or consisting of SEQ ID NO:P162; CDR2 comprising or consisting of SEQ ID NO: P163; and CDR3 comprising or consisting of SEQ ID NO:P164); xxvi. CDR1 comprising or consisting of SEQ ID NO:P170; CDR2 comprising or consisting of SEQ ID NO: P171; and CDR3 comprising or consisting of SEQ ID NO:P172); and xxvii. CDR1 comprising or consisting of SEQ ID NO:P178; CDR2 comprising or consisting of SEQ ID NO: P179; and CDR3 comprising or consisting of SEQ ID NO:P180; and (b) a heavy chain domain (HC) comprising a variable heavy (VH) chain domain comprising of any one of: i. CDR1 comprising or consisting of SEQ ID NO:68 or 88; CDR2 comprising or consisting of SEQ ID NO: 69; and CDR3 comprising or consisting of SEQ ID NO:70; ii. CDR1 comprising or consisting of SEQ ID NO:78; CDR2 comprising or consisting of SEQ ID NO:79; and CDR3 comprising or consisting of SEQ ID NO:80; iii. CDR1 comprising or consisting of SEQ ID NO:88; CDR2 comprising or consisting of SEQ ID NO:89; and CDR3 comprising or consisting of SEQ ID NO:90;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017iv. CDR1 comprising or consisting of SEQ ID NO:98; CDR2 comprising or consisting of SEQ ID NO:99; and CDR3 comprising or consisting of SEQ ID NO: 100; v. CDR1 comprising or consisting of SEQ ID NO:P6; CDR2 comprising or consisting of SEQ ID NO:P7; and CDR3 comprising or consisting of SEQ ID NO:P8; vi. CDR1 comprising or consisting of SEQ ID NO: P14; CDR2 comprising or consisting of SEQ ID NO: P15; and CDR3 comprising or consisting of SEQ ID NO:P16; vii. CDR1 comprising or consisting of SEQ ID NO:P22; CDR2 comprising or consisting of SEQ ID NO: P23; and CDR3 comprising or consisting of SEQ ID NO:P24; viii. CDR1 comprising or consisting of SEQ ID NO:P30; CDR2 comprising or consisting of SEQ ID NO: P31; and CDR3 comprising or consisting of SEQ ID NO:P32; ix. CDR1 comprising or consisting of SEQ ID NO:P38; CDR2 comprising or consisting of SEQ ID NO: P39; and CDR3 comprising or consisting of SEQ ID NO:P40; x. CDR1 comprising or consisting of SEQ ID NO:P46; CDR2 comprising or consisting of SEQ ID NO: P47; and CDR3 comprising or consisting of SEQ ID NO:P48; xi. CDR1 comprising or consisting of SEQ ID NO:P54; CDR2 comprising or consisting of SEQ ID NO: P55, and CDR3 comprising or consisting of SEQ ID NO:P56; xii. CDR1 comprising or consisting of SEQ ID NO:P62; CDR2 comprising or consisting of SEQ ID NO: P63; and CDR3 comprising or consisting of SEQ ID NO:P64; xiii. CDR1 comprising or consisting of SEQ ID NO:P70; CDR2 comprising or consisting of SEQ ID NO: P71; and CDR3 comprising or consisting of SEQ ID NO:P72; xiv. CDR1 comprising or consisting of SEQ ID NO:P78; CDR2 comprising or consisting of SEQ ID NO: P79; and CDR3 comprising or consisting of SEQ ID NO:P80;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xv. CDR1 comprising or consisting of SEQ ID NO:P86; CDR2 comprising or consisting of SEQ ID NO: P87; and CDR3 comprising or consisting of SEQ ID NO:P88; xvi. CDR1 comprising or consisting of SEQ ID NO:P94; CDR2 comprising or consisting of SEQ ID NO: P95; and CDR3 comprising or consisting of SEQ ID NO:P96; xvii. CDR1 comprising or consisting of SEQ ID NO:P102; CDR2 comprising or consisting of SEQ ID NO: P103; and CDR3 comprising or consisting of SEQ ID NO:P104; xviii. CDR1 comprising or consisting of SEQ ID NO:P110; CDR2 comprising or consisting of SEQ ID NO: P111; and CDR3 comprising or consisting of SEQ ID NO:P112; xix. CDR1 comprising or consisting of SEQ ID NO:P118; CDR2 comprising or consisting of SEQ ID NO: P119; and CDR3 comprising or consisting of SEQ ID NO: P120; xx. CDR1 comprising or consisting of SEQ ID NO:P126; CDR2 comprising or consisting of SEQ ID NO: P127; and CDR3 comprising or consisting of SEQ ID NO:P128; xxi. CDR1 comprising or consisting of SEQ ID NO:P134; CDR2 comprising or consisting of SEQ ID NO: P135; and CDR3 comprising or consisting of SEQ ID NO:P136; xxii. CDR1 comprising or consisting of SEQ ID NO:P142; CDR2 comprising or consisting of SEQ ID NO: P143; and CDR3 comprising or consisting of SEQ ID NO:P144; xxiii. CDR1 comprising or consisting of SEQ ID NO:P150; CDR2 comprising or consisting of SEQ ID NO: P151; and CDR3 comprising or consisting of SEQ ID NO:P152; xxiv. CDR1 comprising or consisting of SEQ ID NO:P158; CDR2 comprising or consisting of SEQ ID NO: P159; and CDR3 comprising or consisting of SEQ ID NO:P160; xxv. CDR1 comprising or consisting of SEQ ID NO:P166; CDR2 comprising or consisting of SEQ ID NO: P167; and CDR3 comprising or consisting of SEQ ID NO:P168;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xxvi. CDR1 comprising or consisting of SEQ ID NO:P174; CDR2 comprising or consisting of SEQ ID NO: P175; and CDR3 comprising or consisting of SEQ ID NO:P176; and xxvii. CDR1 comprising or consisting of SEQ ID NO:P182; CDR2 comprising or consisting of SEQ ID NO: P183; and CDR3 comprising or consisting of SEQ ID NO:P184. A useful SPP1 Ab can also comprise a VL domain comprising or consisting of: DIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVP DRFSSSGSGTDFTLRISRVEAEDVGFYYCAQNLELPWTFGGGSKLEIK (SEQ ID NO:P1 (CDRs underlined)) and having CDR1: KSLLHSNGITY (SEQ ID NO:P2); CDR2: LLIYQMS (SEQ ID NO:P3); and CDR3: AQNLELPWT (SEQ ID NO:P4); and a VH domain comprising or consisting of QVQLQQPGAELVNPGASVRLSCKASGYIFTSYWMHWIKQRPGQGLEWIGEINPTSGRTNYNA PFKNKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARLTGTGFYWGQGTLVTVSA (SEQ ID NO:P5 (CDRs underlined)) and having CDR1: GYIFTSYW (SEQ ID NO:P6); CDR2 INPTSGRT (SEQ ID NO:P7); and CDR3: ARLTGTGFY (SEQ ID NO:P8). In some embodiments, the SPP1 antibody comprises: a variable light chain comprising the amino acid sequence of any one of SEQ ID NOs:61, 62, 71, 72, 81, 82, 91, 92, P1, P9, P17, P25, P33, P41, P49, P57, P65, P73, P81, P89, P97, P105, P113, P121, P129, P137, P145, P153, P161, P169, P177, and variants thereof with 1-5 single amino acid modifications (e.g., 1, 2, 3, 4, or 5 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs; and a variable heavy chain comprises the amino acid sequence of any one of SEQ ID NOs:66, 67, 76, 77, 86, 87, 96, 97, P5, P13, P21, P29 , P37 , P45 , P53 , P61 , P69, P77 , P85 , P93, P101, P109, P117, P125, P133, P141, P149, P157, P165, P173, P181, and variants thereof with 1-5 single amino acid modifications (e.g., 1, 2, 3, 4, or 5 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs. In some embodiments, the SPP1 Ab comprises comprise a VL domain comprising or consisting of an amino acid sequence of any one of the VL sequences listed in Table 6, or a variant thereof with 1-5 single amino acid modifications (e.g., 1, 2, 3, 4, or 5 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs; and a VH domain comprisingAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017or consisting of an amino acid sequence of any one of the VH sequences listed in Table 6, or a variant thereof with 1-5 single amino acid modifications (e.g., 1, 2, 3, 4, or 5 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs. A useful SPP1 Ab can also comprise a light chain (LC) domain comprising or consisting of: DIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVP DRFSSSGSGTDFTLRISRVEAEDVGFYYCAQNLELPWTFGGGSKLEIKRADAAPTVSIFPPSSE QLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEY ERHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO:213 (CDRs underlined)) and having CDR1 comprising or consisting of SEQ ID NO:P2; CDR2 comprising or consisting of SEQ ID NO:P3; and CDR3 comprising or consisting of (SEQ ID NO:P4); and a heavy chain (HC) domain comprising or consisting of QVQLQQPGAELVNPGASVRLSCKASGYIFTSYWMHWIKQRPGQGLEWIGEINPTSGRTNYNA PFKNKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARLTGTGFYWGQGTLVTVSAAKTTPPSVY PLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPS STWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVT CVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCR VNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVGWQWNGQ PAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO:214 (CDRs underlined)) and having CDR1 comprising or consisting of SEQ ID NO:P6; CDR2 comprising or consisting of SEQ ID NO:P7; and CDR3 comprising or consisting of SEQ ID NO:P8. In some embodiments, the SPP1 antibodies described herein bind to human OPN. Additional anti-SPP1 antibodies are described in: Fan, K. et al. A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice. European journal of pharmacology 657, 144–151, https: / / doi.org / 10.1016 / j.ejphar.2011.01.041 (2011); Hirano, Y., Aziz, M., Yang, W. L., Ochani, M. & Wang, P. Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion. Shock 46, 431–438, https: / / doi.org / 10.1097 / SHK.0000000000000611 (2016); Yamamoto, N. et al. Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody. International immunopharmacology 7, 1460–1470, https: / / doi.org / 10.1016 / j.intimp.2007.06.009 (2007); Yamamoto, N. et al. Essential role of theAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis. The Journal of clinical investigation 112, 181–188, https: / / doi.org / 10.1172 / JCI17778 (2003); Zhang, B. et al. Anti-osteopontin monoclonal antibody prevents ovariectomy-induced osteoporosis in mice by promotion of osteoclast apoptosis. Biochemical and biophysical research communications 452, 795–800, https: / / doi.org / 10.1016 / j.bbrc.2014.08.149 (2014); Shojaei, F. et al. Osteopontin induces growth of metastatic tumors in a preclinical model of non- small lung cancer. Journal of experimental & clinical cancer research: CR 31, 26, https: / / doi.org / 10.1186 / 1756-9966-31-26 (2012); Dai, J. et al. A humanized anti-osteopontin antibody inhibits breast cancer growth and metastasis in vivo. Cancer immunology, immunotherapy: CII 59, 355–366, https: / / doi.org / 10.1007 / s00262-009-0754-z (2010); and Kazanecki, C. C., Kowalski, A. J., Ding, T., Rittling, S. R. & Denhardt, D. T. Characterization of anti-osteopontin monoclonal antibodies: Binding sensitivity to post-translational modifications. Journal of cellular biochemistry 102, 925–935, https: / / doi.org / 10.1002 / jcb.21487 (2007). Other SPP1 antibodies include: Ab214055, Ab166709, Ab214050, Ab236213 and Ab269441 (ThermoFisher); 2) hu1A12 (Absolute Antibody). SPP1 antibodies are also described in US 2023 / 0203193; WO 2011 / 021146; and US 11897950. CAR Targeting Solid Tumors (e.g., IL-13 CAR) Described herein, inter alia, are IL13Rα2 targeted CAR that can be used conjunction with SPP1 antibody to treat a variety of cancers, including glioblastoma. The IL13Rα2 targeted CAR include all or a portion of mature human IL13 or a variant thereof as a targeting domain. A CAR that includes a variant IL13 is referred to as a “variant IL13 CAR” or simply an IL13 CAR or IL13Rα2 CAR. The variant IL13 can include various mutations (e.g., E11Y, E11R, E90L, and R107K) relative to the sequence of human IL13: GPVPPSTA LRELIEELVN ITQNQKAPLC NGSMVWSINL TAGMYCAALE SLINVSGCSA IEKTQRMLSG FCPHKVSAGQ FSSLHVRDTK IEVAQFVKDL LLHLKKLFRE GRFN (SEQ ID NO: 1) Full sequence of wild-type human IL13 (signal sequence underlined) 10 20 30 40 50 MHPLLNPLLL ALGLMALLLT TVIALTCLGG FASPGPVPPS TALRELIEEL 60 70 80 90 100 VNITQNQKAP LCNGSMVWSI NLTAGMYCAA LESLINVSGC SAIEKTQRML 110 120 130 140Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017SGFCPHKVSA GQFSSLHVRD TKIEVAQFVK DLLLHLKKLF REGRFN (SEQ ID NO: 13) The E90L mutation increases specificity for IL13Ra2 relative to IL13Ra1. Thus, this mutation can be combined with additional mutations, for example one or more of E11Y, E11R, and R107K. A useful IL-13 variant for inclusion in a CAR can comprise 107, 108, 109, 110, 111 contiguous amino acids of SEQ ID NO: 1 or the entirety of SEQ ID NO: 1 with 1, 2, 3, 4 or 5 single amino acid changes, provided that there is not an E at position 90 of SEQ ID NO:1. Thus, position 90 can be selected from: G, A, L, P, V, I, M, F, Y, W, S, T, C, N, Q, K, R, and H; or can be selected from: G, A, L, P, V, I, M, F, Y, W, S, T, C, N, and Q; or can be selected from: G, A, L, P, V, I, M, F, Y and W; or can be selected from: G, A, L, P, V, I and M; or can be selected from: G, A, L, V, I and M. A useful IL-13 variant for inclusion in a CAR can comprise 107, 108, 109, 110, 111 contiguous amino acids of SEQ ID NO: 1 or the entirety of SEQ ID NO: 1 with 1, 2, 3, 4 or 5 single amino acid changes, provided that there is an L at position 90 of SEQ ID NO:1. Thus, position 90 can be selected from: G, A, L, P, V, I, M, F, Y, W, S, T, C, N, Q, K, R, and H; or can be selected from: G, A, L, P, V, I, M, F, Y, W, S, T, C, N, and Q; or can be selected from: G, A, L, P, V, I, M, F, Y and W; or can be selected from: G, A, L, P, V, I and M; or can be selected from: G, A, L, V, I and M. The variant IL13 CAR described herein include a variant IL-13 comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“YLK”; SEQ ID NO: 2); or comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“RLK”; SEQ ID NO: 3); or comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“RL”; SEQ ID NO:4);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017or comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“YL”; SEQ ID NO: 5); or comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“LK”; SEQ ID NO: 6); or comprising or consisting of the amino acid sequence (mutation compared to wt IL13 is bold and double underline): GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN (“R’; SEQ ID NO: 7); or comprising or consisting of the amino acid sequence (mutation compared to wt IL13 is bold and double underline): GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“L”; SEQ ID NO: 8); or comprising or consisting of the amino acid sequence (mutations compared to wt IL13 are bold and double underline): GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGRFN (“K”; SEQ ID NO: 9); or comprising or consisting of the amino acid sequence: GPVPPSTAVRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTRIEVAQFVKDLLNHLKELFTEGQFN (“C4”; SEQ ID NO: 10) or comprising or consisting of the amino acid sequence: PGPVPPSTAARELIEELFNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTKR MLSGFCPHKVSAGQFPSLHVKKTRIEVAQFVKDLLIHLRKLFKEGQFN (“D7”; SEQ ID NO: 11) or comprising or consisting of the amino acid sequence: GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN (“E”; SEQ ID NO: 12).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017In some embodiments, the CAR comprise a chlorotoxin (CLTX). A CLTX can comprise or consist of the amino acid sequence: MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR (SEQ ID NO:14) or a variant thereof having 1-5 (e.g., 1 or 2) single amino acid modifications (e.g., substitutions) provided that the cysteine residues are not modified. Additional information, including CLTX variants and related toxins (such as GaTx2 & GaTx1, toxins from Leiurus quinquestriatus hebraeus, AaCtx, a toxin from Androctonus australis, etc.) as well as methods of making and using CLTX CAR and immune cells expressing CLTX CAR, are known in the art; e.g., WO 2017 / 066481. Described herein, inter alia, are CAR targeted to an antigen expressed on the surface of a cancer cell (e.g., IL13Ra2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA) that can be used conjunction with SPP1 antibody to treat a variety of cancers, including gliomas such as glioblastoma, solid tumors, and cancers comprising cells expressing any one of IL13Ra2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA. The IL13Rα2 targeted CAR can include all or a portion of mature human IL13 or a variant thereof as a targeting domain. The MMP2 targeted CAR can include all or a portion of a cholorotoxin (e.g., SEQ ID NO:14) or a variant thereof as a targeting domain. In some embodiments, the CAR can comprise an scFv targeted to a solid tumor (e.g., EGFR / EGFRvIII, B7H3, TAG72, CD70, HER2, PSCA, and PSMA). The targeting domain can comprise or consist of a scFv targeted to HER2 (also called ErbB2). In some embodiments, the HER2 scFv comprises or consists of the amino acid sequence of any one of SED ID NO: 205-208 and variants thereof having no more than 1, 2, 3, 4 or 5 single amino acid modifications (e.g., substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs. Additional HER2 targeting sequences (e.g., HER2 CDRs, HER2 variable domains (i.e., VL and VH), and HER2 scFvs) and HER2 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., 4D5, rastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, margetuximab, pertuzumab, disitamab vedotin, U-31402, ISU-104, SIB-001, 9F7- F11, EV-20Sap, U-31402, ARX-788, BAT-8001, HL-02, TAA-013, trastuzumab duocarmazine, A-166, AU-101, AU-105, BPX-603, ISB-1302, KN-026, MB-103, MRG-002, zanidatamab, zenocutuzumab, ACE-1702, ALTP-7, B-002, BAT-8001, BAT-1006, BAY-2701439, BTRC- 4017A, CAMH-2, cinrebafusp alfa, CT-0508, DP-303c, DX-126262, FS-102, FS-1502, GQ-Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-0171001, HS-630, LCB-14, M-802, MBS-301, MT-5111, NJH-395, PF-06804103, SBT-6050, SENL- 006, SHRA-1201, SHRA-1811, TT-16, ZW-49; LZM-006; HER2Bi-armed ATC (Roger Williams Medical Center); WO 2017 / 079694; WO 2024 / 129964; WO 2023 / 196893; US 2024 / 0299543 A1; US Pat. No.11,161,907 (also called ErbB2 and 4D5 therein); Liu X, Zhang N, Shi H. (2017) Oncotarget.8(37):62730-62741; Jiangang Sun, et. al. (2022) Journal of Inflammation Research, 15: 4061-4085. The targeting domain can comprise or consist of a scFv targeted to an epidermal growth factor receptor (EGFR), a truncated EGFR (EGFRt), a variant of EGFR (e.g., epidermal growth factor receptor variant III; EGFRvIII), or the extracellular binding domain of EGFR. In some embodiments, the EGFR scFv targets both wild-type EGFR and EGFRvIII. In some embodiments, the EGFR scFv comprises or consists of the amino acid sequence of SED ID NO: 203 or 204, or a variant thereof having no more than 1, 2, 3, 4 or 5 single amino acid modifications (e.g., substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs. Additional EGFR targeting sequences (e.g., EGFR CDRs, EGFR variable domains (i.e., VL and VH), and EGFR scFvs) and EGFR targeted CAR, as well as methods of making and using the same, are known in the art; e.g., CDRs and sequences of cetuximab, panitumumab, necitumumab, nepidermin, nimotuzumab, amivantamab, HS-627, amelimumab, depatuxizumab, FmAb-2, GC-1118A, imgatuzumab, matuzumab, MVC-101, SCT-200, QL-1203, tomuzotuximab, zalutumumab, JMT-101, MCLA-158, QL-1105, SYN-004, MCLA-129, WBP- 297, AM-105, BH-2922, BMX-002, CMAB-017, DF-203, GB-263, JZB-29, SAH-EJ1, SFR- 9X0122, UBP-1215, ABX-901, MCLA-125, TXB-4BC2, 111-In-ch806, depatuxizumab mafodotin, DR-50201, DXL-1218, ENLS-1, FS-101, GI-3000, and described in WO 2011 / 056894; US 2014 / 0322275; US Pat. No.11,161,907. Additional CD70 targeting sequences (e.g., CD70 CDRs, CD70 variable domains (i.e., VL and VH), and CD70 scFvs) and CD70 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., Xiong, Q., et al. (2024) The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment. J Transl Med 22, 368; US 2023 / 0265147 A1; US 20230399412 A1; US20220411478A1; US20220347217A1; WO 2024 / 086841.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017The targeting domain can comprise or consist of a scFv targeted to PSCA. In some embodiments, the PSCA scFv comprises or consists of the amino acid sequence of SEQ ID NO: 209 or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., substitutions), wherein the modifications are not in the CDRs. Additional PSCA targeting sequences (e.g., PSCA CDRs, PSCA variable domains (i.e., VL and VH), and PSCA scFvs) and PSCA targeted CAR, as well as methods of making and using the same, are known in the art; e.g., WO 2017 / 062628; WO 2022 / 115421; US 2024 / 0041921 A1; Morgenroth et al., (2007) Prostate 67(10):1121-1131 (scFv 7F5); Nejatollahi et al., (2013) J Oncology, article ID 839831 (scFv CS-II); and US 2009 / 0311181 A1. The targeting domain can comprise or consist of a scFv targeted to PSMA. In some embodiments, the PSMA scFv comprises or consists of the amino acid sequence of SEQ ID NO: 210 or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., substitutions), wherein the modifications are not in the CDRs. Additional PSMA targeting sequences (e.g., PSMA CDRs, PSMA variable domains (i.e., VL and VH), and PSMA scFvs) and PSMA targeted CAR, as well as methods of making and using the same, are known in the art; CIK-CAR.PSMA (Formula Pharmaceuticals Inc), P-PSMA-101 (Poseida Therapeutics Inc), UniCAR-T-PSMA (GEMoaB Monoclonals GmbH), Parker et al., Protein Expr Purif 89(2):136- 145 (2013), US 20110268656 (e.g., J591 ScFv); Frigerio et al, European J Cancer 49(9):2223- 2232 (2013) (e.g., scFvD2B); WO 2006125481 (e.g., mAbs 3 / A12, 3 / E7, and 3 / F11 and (scFv A5 and D7). The targeting domain can comprise or consist of a scFv targeted to TAG72. In some embodiments, the TAG72 scFv comprises or consists of the amino acid sequence of SEQ ID NO: 211, or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., substitutions), wherein the modifications are not in the CDRs. Additional TAG-72 targeting sequences (e.g., TAG72 CDRs, TAG72 variable domains (i.e., VL and VH), and TAG72 scFvs) and TAG72 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., WO 2020 / 028721. The targeting domain can comprise or consist of a CD70 binding domain (e.g., a CD70 scFv). In some embodiments, the PSCA scFv comprises or consists of the amino acid sequence of SEQ ID NO: 212 or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modificationsAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017(e.g., single amino acid substitutions), wherein the modifications are not in the CDRs. Additional CD70 targeting sequences (e.g., CD70 CDRs, CD70 variable domains (i.e., VL and VH), and CD70 scFvs) and CD70 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., Xiong, Q., et al. (2024) The development of chimeric antigen receptor T- cells against CD70 for renal cell carcinoma treatment. J Transl Med 22, 368; US 2023 / 0265147 A1; US 20230399412 A1; US20220411478A1; US20220347217A1; WO 2024 / 086841. The targeting domain can comprise or consist of a scFv targeted to B7H3. For example, the B7H3 scFv can comprise the CDRs of antibody MGA271. Many B7H3 targeting sequences (e.g., B7H3 CDRs, B7H3 variable domains (i.e., VL and VH), and B7H3 scFvs) and B7H3 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., antibody MGA271 (Macrogenics); WO 2024 / 061306; WO 2024 / 226468; US20250136697A1; US20240245771A1; US20240252639A1 In some embodiments, the CAR comprise a targeting domain; a spacer comprising a sequence selected from the group consisting of: SEQ ID NOs: 24-34; a transmembrane domain comprising a sequence selected from the group consisting of SEQ ID NOs: 15-23; a costimulatory domain comprising a sequence selected from the group consisting of SEQ ID NOs: 36-40, and a CD3ζ signaling domain comprising SEQ ID NO: 35. In some embodiments, the targeting domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 1-14 and 203-212. The spacer region can include an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-34 or a variant thereof having 1, 2, 3, 4, or 5 amino acid substitutions; the transmembrane domain selected from the group consisting of: a CD4 transmembrane domain, a CD8 transmembrane domain, a CD28 transmembrane domain, and a CD3ζ transmembrane domain; the costimulatory domain selected from the group consisting of: a 28 costimulatory domain, a 41-BB costimulatory domain, an OX40 costimulatory domain, and a 2B4 costimulatory domain. In some embodiments, the nucleic acid molecule further comprises an interdomain linker consisting of 1 - 5 amino acids between one or more of: the targeting domain (e.g., scFv) and the spacer domain, the spacer domain and the transmembrane domain, the transmembrane domain and the co-stimulatory domain, and / or the costimulatory domain and the CD3ζ signaling domain; the interdomain linker can consist of 1-5 glycine; in someAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017embodiments, the CAR further comprises an interdomain linker consisting of the sequence GGG is located between the costimulatory domain and the CD3ζ signaling domain. In some embodiments, the CAR comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 101-212 and variants thereof having 1-15 (e.g., 1, 2, 3, 4, 5, or 6) single amino acid modifications (e.g., substitutions); optionally wherein the amino acid modifications (e.g., substitutions) are not in the targeting domain; optionally wherein the amino acid modifications (e.g., substitutions) are not in the CDRs of the scFv. Also disclosed herein are vectors (e.g., viral vectors) comprising a nucleic acid molecule described herein (e.g., a nucleic acid encoding an SPP1 antibody, a nucleic acid comprising a CAR); populations of immune cells comprising a vector comprising a nucleotide sequence described here; populations of immune cells expressing a CAR described here; populations of human T cells (e.g., a population comprising central memory T cells) and / or of human NK cells transduced by a vector comprising a nucleic acid molecule described herein. In some embodiments, the T cells comprise PBMC, dPBMC (PBMC with depletion of CD14+ and CD25+ cells), Tn / mem (naïve and memory T cells, CD62L+ enriched from dPBMC), or Tcm (central memory T cells). Additional information, including methods of making and using CAR and immune cells expressing CAR, are known in the art; e.g., WO 2017 / 015490; WO 2017 / 066481; WO 2017 / 136829; WO 2018 / 102761; WO 2023 / 107593; US 2024 / 0398913 A1; US 2023 / 0295296 A1. In various embodiments: a population of immune cell can comprise one or more of helper T cells, cytotoxic T cells, memory T cells, naïve T cells, regulatory T cells, natural killer T cells, or combinations thereof. In various embodiments: at least 20%, 30%, 40%, or 50% of the CAR T cells are CD8+ T cells. Various T cell subsets, including both alpha beta T cells and gamma delta T cells, can be used. In addition, the CAR can be expressed in other immune cells such as NK cells. Where a patient is treated with an immune cell expressing a CAR described herein the cell can be an autologous T cell or an allogenic T cell. In some cases, the cells used are a cell population that includes both CD4+ and CD8+ central memory T cells (TCM), which are CD62L+, CCR7+, CD45RO+, and CD45RA-, or the cells used are a cell population that includes CD4+ and CD8+ TCMcells, stem central memory T cells and naïve T cells (i.e., a population of TCM / SCM / N cells). A population of TCM / SCM / N cells are CD62L+, CCR7+ and include both CD45RA+ and CD45RO+ cells as well as both CD4+ cells and CD8+ cells. The use of such cells canAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017improve long-term persistence of the cells after adoptive transfer compared to the use of other types of patient-specific T cells. In some embodiments, a composition comprising CAR T cells or CAR NK cells described herein is administered locally or systemically. In some embodiments, a composition comprising CAR T cells or CAR NK cells described herein is administered by single or repeat dosing. In some embodiments, a composition comprising CAR T cells or CAR NK cells described herein is administered to a patient having a glioma (e.g., glioblastoma)..- In some embodiments, a composition comprising CAR T cells or CAR NK cells described herein is administered to a patient having a solid tumor. In some embodiments, a composition comprising CAR T cells or CAR NK cells described herein is administered to a patient having a cancer comprising cells expressing SPP1, An amino acid modification refers to an amino acid substitution, insertion, and / or deletion in a protein or peptide sequence. An “amino acid substitution” or “substitution” refers to replacement of an amino acid at a particular position in a parent peptide or protein sequence with another amino acid. A substitution can be made to change an amino acid in the resulting protein in a non-conservative manner (i.e., by changing the codon from an amino acid belonging to a grouping of amino acids having a particular size or characteristic to an amino acid belonging to another grouping) or in a conservative manner (i.e., by changing the codon from an amino acid belonging to a grouping of amino acids having a particular size or characteristic to an amino acid belonging to the same grouping). Such a conservative change generally leads to less change in the structure and function of the resulting protein. The following are examples of various groupings of amino acids: 1) Amino acids with nonpolar R groups: Alanine, Valine, Leucine, Isoleucine, Proline, Phenylalanine, Tryptophan, Methionine; 2) Amino acids with uncharged polar R groups: Glycine, Serine, Threonine, Cysteine, Tyrosine, Asparagine, Glutamine; 3) Amino acids with charged polar R groups (negatively charged at pH 6.0): Aspartic acid, Glutamic acid; 4) Basic amino acids (positively charged at pH 6.0): Lysine, Arginine, Histidine (at pH 6.0). Another grouping may be those amino acids with phenyl groups: Phenylalanine, Tryptophan, and Tyrosine. CDR regions are well known to those skilled in the art and have been defined by well-known numbering systems. Generally, the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops. By usingAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., supra; Nick Deschacht et al., (2010) J Immunol.184:5696-5704). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk (1987) J. Mol. Biol.196:901-17). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). Correspondence between the numbering systems, including, for example, the Kabat numbering and the ImMunoGeneTics (IMGT) Information System (Lafranc et al., (2003) Dev. Comp. Immunol.27(1):55-77) numbering system, is well known to one skilled in the art. Accordingly, one or ordinary skill in the art is able to discern the CDRs of given targeting sequences and adjust them according to the differing numbering systems. For example, the residues from each hypervariable region / CDR are exemplified in Table 5 below. Table 5. Exemplary CDRs According to Differing Numbering Systems Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG.1: Suppressive tumor microenvironment limits response to CAR T therapy in high- grade glioma a. Schematic illustration of the Phase I trial and sample processing. b. Numbers of glioblastoma tumors (41 total patient samples) with high (3-4) or low (0-2) immunohistochemistry CD3 scores and samples that did or did not respond to CAR T therapy. c. UMAP dimensionality reduction of 52,751 cells from 41 donors pseudocolored by cluster identity. d. Proportions of cells annotated for each cluster across tumor samples from the 41 donors. e. Clustering of 28,156 immune and stromal cells. f. Expression of marker features among the immune and stromal cells and expression status of discriminating features for each cluster. g. Differences in immune and stromal cell type proportions between complete response / stable disease (CR / SD) and progressive disease (PD) and GBM tumors with high (3-4) and low (0-2) IHC CD3 scores. Log2 fold difference with confidence intervals are presented. Results for cell types with significant differences based on a permutation p-value are highlighted. * indicates that M8 was only found in CD3 low tumors. h. Differentially regulated ligand-receptor signaling pathways in immune subclusters of the TME, comparing SD / CR vs. PD tumors (top) and CD3-med / high vs, CD3-low tumors (bottom). Significant pathways were selected with a two-sided Wilcoxon p < 0.01 in the comparison of SD / CR vs. PD, and pathways with an absolute delta of information flow > 0.8 were plotted, with positive values indicating increased signaling in PD or CD3-low tumors. The information flow for a given signaling pathway is defined by the sum of communication probability among all pairs of cell groups in the inferred network. i. Differential SPP1 signaling interaction strength between all pairs of analyzed cell types in a comparison of SD / CR and PDAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017tumors. Positive values indicate increased signaling in PD tumors. j. Schematic depiction of the top three cell-cell communication pathways in PD tumors compared to SD / CR tumors. FIG.2: Characterization of SPP1 expressing macrophages in non-responders to IL13R2 targeted therapies a. Hazard ratios for survival by expression of macrophage markers CD14, CD68, C1QC, C1QB, C1QA, and SPP1 in a cohort of 41 patients. The HRs and 95% confidence intervals are shown. SPP1 expression significantly correlates with survival outcomes (HR = 1.02, p < 0.001), emphasizing its greater predictive relevance compared to other markers. b. Violin plots displaying the differential expression levels of SPP1 across various macrophage subclusters, comparing samples PD (right) to those with CR / SD (left), and samples with CD3 low (right) to those with CD3 high expression (left). c. Scatter plot depicting the relationship between SPP1 expression levels and survival months post-surgery for individual patients, identified by their anonymized codes. The bar graph to the right depicts differential proportions of myeloid and lymphoid cells in the immune cell fraction of SPP1 High and SPP1 Low GBM / HGG tumors (Χ2= 9.23 p-value = 0.002). d. Forest plot representing the distribution of subclusters among patients from the top and bottom marked areas in FIG 2C. e. Violin plots displaying differential expression of various markers involved in antigen presentation and functionality of macrophages between SPP1 high and low SPP1 macrophages. f. Pathway enrichment analysis revealing the differential expression of pathways involved in lower antigen presentation, lower phagocytosis, higher ECM synthesis and remodeling, lower inflammatory cytokines in SPP1 high (lower portion) versus SPP1 low (upper portion) expressing macrophages. g. Pathway enrichment analysis depicting SPP1 high macrophages are lipid associated macrophages. h. Immunofluorescent staining showing higher expression of SPP1 in PD patients compared to the control group. f. Immunofluorescent staining for SPP1, COL1A1, and CD68 shows a higher expression of SPP1 and enrichment of fibroblasts in PD tumors compared to SD / CR tumors. Bars indicate 50 µm. g. Mean ± SD. SPP1-expressing cell counts by immunofluorescent staining of tumor sections in g. from patients that exhibited either SD / CR (n = 5) or PD (n = 6). ROI = 2 mm2, **, p = 0.02 using an unpaired t-test. k. Expression of SPP1 in GBM / HGG whole tumors is negatively correlated with survival (n = 37, R2= 0.13, p = 0.03). l. Cox’s proportional-hazard ratio (HR) for survival by the proportion (%) of myeloid cells expressing SPP1 (SPP1int / hi) in a cohort of 41 GBM / HGG patients. The HR = 1.04 (CI = 1.01– 1.11, p = 0.002) indicating 4% increased risk with 1% increase in the relative abundance of SPP1himyeloid cells, is shown.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017FIG.3: Congruent pathways drive the suppressive tumor microenvironment in glioblastoma and a syngeneic mouse model a. Schematic illustration of the integration analysis of single-cell RNA sequencing data from patient GBM tumor samples and mouse YUMM JAK1 / KO tumor samples, CD45+ immune and stromal cells from 41 GBM tumors and 4 YUMM JAK1KO mouse melanomas were integrated to examine regulatory programs shared with the two tumor types. b. Clustering of 68,480 cells across 13 myeloid, four lymphoid, and six stromal cell types from GBM (28,156 cells) and 28,156 JAK1KO (28,156 cells). c. Correlation of the average expression of immune and fibroblast marker genes between GBM tumors (PD) and JAK1KO YUMM tumors (left), in comparison with GBM tumors (SD / CR) and WT YUMM tumors (right), R2 is indicated for each comparison. d. Schematic illustration depicting the design if a study for in vivo evaluation of mIL13Ra2 CAR T cell therapy against YUMM JAK1 / KO and WT tumors. e. Tumor volumes post mIL13Ra2 treatment comparing significant response in YUMM WT tumors to suboptimal response in YUMM JAK1KO tumors. f. UMAP plot depicting the sc-RNA seq clusters in JAK1 / KO and WT tumors g. Forest plot comparing the distribution of clusters between YUMM JAK1 / KO and WT tumors post mIL13Ra2 CAR T cell therapy. h. Significantly higher expression of SPP1 in TME subclusters of YUMMJAK1 / KO tumors (left) compared to YUMM WT tumors (right) post mIL13Ra2 CAR T cell therapy. i. CyTOF analysis of TME in YUMMJAK1 / KO tumor compared to YUMM WT tumors post mIL13Ra2 CAR T cell therapy. FIG.4: Priming of YUMM JAK1 / KO tumors with SPP-1 targeted monoclonal antibody before delivering mIL13 CAR T cells significantly enhances therapeutic efficacy a. Schematic illustration of the experimental design of a study combining anti-SPP1 antibody and mIL13Ra2 CAR T cell therapy against YUMM JAK1 / KO tumors. b. Tumor volumes comparing combination therapy to mIL13Ra2 CAR T cell therapy alone and anti-SPP1 antibody treatment alone. c. Bulk RNAseq cell type deconvolution data from mice treated with a combination of anti-SPP1 antibody and mIL13Ra2 CAR T, mIL13Ra2 CAR T alone, or anti- SPP1 antibody alone, and compared to control group. d. COL1A1 and SPP1 expression in glioma mouse models. e. Schematic illustration of experimental design of orthotopic glioma model treated with combination of anti-SPP1 antibody and mIL13Ra2 CAR T cell therapy compared to mIL13Ra2 CAR T cell therapy alone. f. Flux values revealed significantly lower bioluminescence values in KLuc harboring mice treated with combination therapy compared to mIL13Ra2 CAR T alone, anti-SPP1 antibody alone treated groups. g. Kaplan-Meier survivalAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017curves. h. Survival analysis revealed significantly longer survival of KLuc harboring mice treated with combination therapy compared to mIL13Rα2 CAR T alone, anti-SPP1 antibody alone treated groups. Data are mean ± SEM. i. Flux values revealed significantly lower bioluminescence values in KLuc harboring mice treated with combination therapy compared to mIL13Rα2 CAR T alone, anti-OPN antibody alone treated groups. h, Mice heads showing the flux values comparing mIL13Rα2 CAR T and anti-OPN antibody combined treated group to mIL13Rα2 CAR T alone group. FIG 5: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD28 TM domain, 41-BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 101-102). FIG 6: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD28 TM domain, 41-BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 103-104). FIG 7: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD28 TM domain, 41-BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 105-106). FIG 8: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD28 TM domain, 41-BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 107-108). FIG 9: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD4 TM domain, CD28 co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 109-110). FIG 10: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD4 TM domain, CD28 co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 111-112). FIG 11: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD4 TM domain, CD28 co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 113-114). FIG 12: Depicts the amino acid sequence of CAR having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD4 TM domain, CD28 co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 115-116).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017FIG 13: Depicts the amino acid sequences of CARs having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD4 TM domain, 4-1BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 117-120). FIG 14: Depicts the amino acid sequences of CARs having: a variant IL13 targeting domain, an IgG4 (EQ) spacer, CD8 TM domain, 41-BB co-stimulatory domain and a CD3zeta domain (SEQ ID NOs: 121-124). FIG 15: Depicts the amino acid sequence of IL13(C4)-IgG4(L235E,N297Q)-CD28gg-Zeta without a signal sequence (SEQ ID NO: 125). FIG 16: Depicts the amino acid sequence of a CAR having C4 mutein targeting domain. Amino acid sequence of IL13(C4)-IgG4(HL-CH3)-CD4tm-41BB-Zeta (SEQ ID NO: 126). FIG 17: Depicts the amino acid sequence of a CAR having D7 mutein targeting domain. Amino acid sequence of IL13(D7)-IgG4(L235E,N297Q)-CD28gg-Zeta (SEQ ID NO: 127). FIG 18: Depicts the amino acid sequence of a CAR having D7 mutein targeting domain. Amino acid sequence of (A) IL13(D7)-IgG4(HL-CH3)-CD4tm-41BB-Zeta (SEQ ID NO: 128). FIG 19: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 129; without the signal peptide, SEQ ID NO:130). FIG 20: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 131; without the signal peptide, SEQ ID NO:132). FIG 21: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 133; without the signal peptide, SEQ ID NO:134). FIG 22: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 135; without the signal peptide, SEQ ID NO:136). FIG 23: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 137; without the signal peptide, SEQ ID NO:138). FIG 24: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 139; without the signal peptide, SEQ ID NO:140). FIG 25: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 141; without the signal peptide, SEQ ID NO:142). FIG 26: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 143; without the signal peptide, SEQ ID NO:144).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017FIG 27: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 145; without the signal peptide, SEQ ID NO:146) FIG 28: Depicts that amino acid sequence of and IL-13 CAR having a variant IL-13 targeting domain (SEQ ID NO: 147; without the signal peptide, SEQ ID NO:148). FIG.29A-29M. Characterization of IFN signaling-deficient tumor mouse model displaying resistance to mIL13Rα2 CAR T cell therapy. a, Schematic illustration of the study design for in vivo evaluation of systemic mIL13Rα2 CAR T cell therapy (IV) against YUMM WT (n = 5) vs. JAK1 / KO (n = 5) tumor bearing mice. b, Differential tumor growth dynamics of YUMM JAK1 / KO tumors compared to YUMM WT to systemic mIL13Rα2 CAR T cell therapy (IV).95% confidence intervals are depicted; significant differential tumor growth is denoted with asterisks (** p<0.01). c, Flow cytometric analysis shows a significantly reduced percentage of CD3+ cells in the blood of mice bearing YUMM JAK1 / KO tumors treated with mIL13Rα2 CAR T cells compared to YUMM WT (** p<0.01). Data are mean ± SD. d, Flow cytometric analysis showing reduced CAR T cell percentages in the blood of YUMM JAK1 / KO tumor-bearing mice compared to YUMM WT (* p<0.05). Data are mean ± SD. e, Schematic illustration of the study design for in vivo evaluation of intra-tumoral mIL13Rα2 CAR T cell therapy against WT (n=7) vs. JAK1 / KO (n=7) YUMM tumor bearing mice. f, Volumes of tumors untreated or treated with mIL13Rα2 CAR T cells, exhibiting significant response in YUMM WT tumors in comparison to suboptimal response in YUMM JAK1 / KO tumors (* p<0.05). Data are mean ± SEM. g, Clustering of scRNA-seq data of 51,820 CD45+ cells from 6 JAK1 / KO (23,848 cells, including 14,831 cells from mIL13Rα2 CAR T treated and 9,017 cells from untreated control tumors) and 6 WT (27,972 cells, 14,128 treated, 13,844 untreated) tumors, annotated by cluster identity. h, Differences in cell type distribution between YUMM JAK1 / KO and YUMM WT tumors untreated (left) or treated with mIL13Rα2 CAR T cell therapy (right). Log2 fold-differences with 95% confidence intervals are presented. Results for cell types with significant differences based on a permutation p-value are highlighted in red. i, T cell counts in scRNA-seq data reveal reduced infiltration of CD3+ T cells in JAK1 / KO YUMM tumors compared to WT counterparts following mIL13Rα2 CAR T cell treatment. j, The percentage of mIL13Rα2 CAR T cells identified in scRNA-seq analysis shows a reduction in JAK1 / KO YUMM tumors relative to WT YUMM tumors. k, Differentially regulated ligand-receptor signaling pathways in a comparison of the TME of CAR treated YUMM JAK1 / KO and WT tumors. Significant pathways were selected with a p<0.01, and pathways with an absolute delta of >0.8 were selected for plotting. The information flow for a given signaling pathway is defined by the sum of communicationAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017probability among all pairs of cell groups in the inferred network. Delta of the overall information flow between groups in each comparison is presented, with positive values indicating increased signaling in JAK1 / KO. l, Differential strength of interactions between all pairs of analyzed cell types in a comparison of CAR treated JAK1 / KO and WT tumors. Positive values indicate increased signaling in JAK1 / KO. m, SPP1 and CD44 are upregulated across TME subclusters of YUMM JAK1 / KO tumors compared to YUMM WT tumors after mIL13Rα2 CAR T cell therapy. Log-normalized SPP1 expression is stratified by JAK1 and treatment status. Significant differential expression is denoted with asterisks: * p<0.05, ** p<0.01, *** p<0.001. FIG.30A. Schematic illustration of the integrated analysis of scRNA-seq data from patient GBM / HGG and mouse YUMM JAK1 / KO tumors. Immune and stromal cells from human GBM / HGG (n = 41) and YUMM JAK1 / KO mouse melanoma tumors (n = 4) were jointly analyzed to examine regulatory programs shared between the two tumor types. FIG. 30B, UMAP dimensionality reduction of GBM / HGG (28,156 cells) and YUMM JAK1 / KO (40,324 cells) scRNA-seq data, annotated by cluster identity. FIG.30C, Expression of canonical myeloid and fibroblast markers (presented in Fig.1f) are highly correlated (R2= 0.55) between GBM / HGG and JAK1 / KO YUMM tumors in relevant cell types. Colors of cell types correspond to Fig.1f. Subsets of highly expressed genes are notated. Regression lines with confidence intervals are depicted for each gene–cell type combination. FIG.30D, Expression of selected markers (as in panel c) between the TME subsets of GBM / HGG tumors with best response of Progressive Disease and JAK1 / KO YUMM tumors (R2= 0.41). FIG.30E, Expression of selected markers (as in panel c) is poorly correlated (R2= 0.04) between the TME subsets of GBM / HGG and JAK1 / WT YUMM tumors. FIGS.31A-31B. Anti-SPP1 mAb restores SPP1-mediated inhibition on proliferation and activation of CAR T cell. FIG.31A. Human IL13Rα2-CAR T cell stained by CFSE was activated by 2.5 µg / mL anti-CD3 and incubated with indicated concentration of rhSPP1. FIG. 31B. Indicated concentration of anti-SPP1 mAb was added to human IL13Rα2-CAR T cell stained by CFSE and activated by 2.5 µg / mL anti-CD3 and incubated with 10 µg / mL rhSPP1 or not. Cell proliferation and activation (measured by CD69+CD25+) was detected by flow cytometry. Anti-SPP1 mAb used in these experiments is obtained from BioXCell (InVivoMAb anti-mouse / human / rat SPP1, Catalog #BE0382, Clone: MPIIIB10) FIG.32. SPP1 inhibits IL13Ra2-Fc-mediated CAR T cell activation and proliferation. Human IL13Rα2-CAR T cell stained by CFSE was activated by indicated amount of human IL13Rα2-Fc or 2.5 µg / mL anti-CD3 and incubated with 10 µg / mL recombinant human SPP1 orAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017not. Cell proliferation and activation (measured by CD69+41BB+) was detected by flow cytometry. FIG.33. Sequence of anti-mouse / human / rat SPP1 Ab. The sequence of the light chain (SEQ ID NO:213) and heavy chain (SEQ ID NO:214) are shown with the CDRs bolded and underlined; the N-link glycosylation site in the heavy chain is also identified (bolded and underlined). FIG.34A depicts the amino acid sequence of CLTX-IgG4(L235E, N297Q)-CD28tm-CD28gg- zeta (SEQ ID NO:149; mature sequence without the signal sequence is SEQ ID NO:150). FIG.34B depicts the amino acid sequence of CLTX-IgG4(HL-CH3)-CD28tm -CD28gg-zeta (SEQ ID NO:151; mature sequence without the signal sequence is SEQ ID NO:152). FIG.34C depicts the amino acid sequence of CLTX-CD8h-CD28tm-CD28gg-zeta (SEQ ID NO:153; mature sequence without the signal sequence is SEQ ID NO:154). FIG.34D depicts the amino acid sequence of CLTX-IgG4(hinge)-CD28tm -CD28gg-zeta (SEQ ID NO:155; mature sequence without the signal sequence is SEQ ID NO:156). FIG.34E depicts the amino acid sequence of CLTX-L--CD28tm-CD28gg-zeta (SEQ ID NO:157; mature sequence without the signal sequence is SEQ ID NO:158). FIG.34F depicts the amino acid sequence of CLTX-IgG4(L235E, N297Q)-CD28tm-CD28gg-4- 1BB-zeta (SEQ ID NO:159; mature sequence without the signal sequence is SEQ ID NO:160). FIG.34G depicts the amino acid sequence of CLTX-IgG4(HL-CH3)-CD28tm -CD28gg-4-1BB- zeta (SEQ ID NO:161; mature sequence without the signal sequence is SEQ ID NO:162). FIG.34H depicts the amino acid sequence of CLTX-CD8h-CD28tm-CD28gg-4-1BB-zeta (SEQ ID NO:163; mature sequence without the signal sequence is SEQ ID NO:164). FIG.34I depicts the amino acid sequence of CLTX-IgG4(hinge)-CD28tm-CD28gg-4-1BB-zeta (SEQ ID NO:165; mature sequence without the signal sequence is SEQ ID NO:166). FIG.34J depicts the amino acid sequence of CLTX-L-CD28tm-CD28gg-4-1BB-zeta (SEQ ID NO:167; mature sequence without the signal sequence is SEQ ID NO:168). FIG.34K depicts the amino acid sequence of CLTX-IgG4(L235E, N297Q)-CD28tm-4-1BB-zeta (SEQ ID NO:169; mature sequence without the signal sequence is SEQ ID NO:170). FIG.34L depicts the amino acid sequence of CLTX-IgG4(HL-CH3)-CD4tm-4-1BB-zeta (SEQ ID NO:171; mature sequence without the signal sequence is SEQ ID NO:172).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017FIG.34M depicts the amino acid sequence of CLTX-CD8h-CD28tm-4-1BB-zeta (SEQ ID NO:173; mature sequence without the signal sequence is SEQ ID NO:174). FIG.34N depicts the amino acid sequence of CLTX-IgG4(hinge)-CD28tm-4-1BB-zeta (SEQ ID NO:175; mature sequence without the signal sequence is SEQ ID NO:176). FIG.34O depicts the amino acid sequence of CLTX-L-CD28tm-4-1BB-zeta (SEQ ID NO:177; mature sequence without the signal sequence is SEQ ID NO:178). FIG.35A depicts the amino acid sequence of HER2 scFv- IgG4(S228P, L235E, N297Q)- CD8tm-41BB-Zeta (SEQ ID NO:179; mature sequence without the signal sequence is SEQ ID NO:180). FIG.35B depicts the amino acid sequence of HER2 scFv- IgG4(S228P, L235E, N297Q)- CD28tm-CD28gg-Zeta (SEQ ID NO:181; mature sequence without the signal sequence is SEQ ID NO:182). FIG.35C depicts the amino acid sequence of HER2 scFv -CD8hinge-CD8tm-41BB-Zeta (SEQ ID NO:183; mature sequence without the signal sequence is SEQ ID NO:184). FIG.35D depicts the amino acid sequence of HER2 scFv - IgG4hinge(S228P)-linker-CD8tm- 41BB-Zeta (SEQ ID NO:185; mature sequence without the signal sequence is SEQ ID NO:186). FIG.35E depicts the amino acid sequence of HER2 scFv - IgG4(S228P)-Linker-IgG4 CH3- CD8tm-41BB-Zeta (SEQ ID NO:187; mature sequence without the signal sequence is SEQ ID NO:188). FIG.35F depicts the amino acid sequence of HER2 scFv - IgG4(S228P)-Linker-IgG4 CH3-CD28tm-CD28gg-Zeta (SEQ ID NO:189; mature sequence without the signal sequence is SEQ ID NO:190). FIG.35G depicts the amino acid sequence of HER2 scFv - Linker-CD28tm-CD28gg-Zeta (SEQ ID NO:191; mature sequence without the signal sequence is SEQ ID NO:192). FIG.35H depicts the amino acid sequence of HER2 scFv - Linker-CD8tm-41BB-Zeta (SEQ ID NO:193; mature sequence without the signal sequence is SEQ ID NO:194). FIG.35I depicts the amino acid sequence of HER2 scFv - CD8h-CD8tm-Zeta (SEQ ID NO:195; mature sequence without the signal sequence is SEQ ID NO:196).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017DETAILED DESCRIPTION IA. SPP1 Antibodies Described herein, inter alia, are antibodies targeted to SPP1 and uses thereof. In some embodiments, SPP1 antibodies can comprise a variable light (VL) chain domain (e.g., any one of the VL listed in Table 6) and a variable heavy (VH) chain domain (e.g., any one of the VH listed in Table 6). In some embodiments, the SPP1 antibody comprises: a VL domain comprising the amino acid sequence of a VL listed in Table 6 or a variant thereof having 1-5 (e.g., 1, 2, or 3) single amino acid modifications (e.g., substitutions), wherein the modifications are not in the CDRs; and a VH domain comprising the amino acid sequence of a VH listed in Table 6 or a variant thereof having 1-5 (e.g., 1, 2, or 3) single amino acid modifications (e.g., substitutions), wherein the modifications are not in the CDRs. In some embodiments, the SPP1 antibody comprises the CDRs of a VL listed in Table 6 and the CDRs of a VH listed in Table 6. Table 6: SPP1 Antibody Sequences Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 A useful SPP1 Ab can also comprise a light chain (LC) domain comprising or consisting of: DIVMTQAAFSNPVTLGTSASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVP DRFSSSGSGTDFTLRISRVEAEDVGFYYCAQNLELPWTFGGGSKLEIKRADAAPTVSIFPPSSE QLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEY ERHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO:213 (CDRs underlined)) and having CDR1 comprising or consisting of SEQ ID NO:P2; CDR2 comprising or consisting of SEQ ID NO:P3; and CDR3 comprising or consisting of (SEQ ID NO:P4); and a heavy chain (HC) domain comprising or consisting of QVQLQQPGAELVNPGASVRLSCKASGYIFTSYWMHWIKQRPGQGLEWIGEINPTSGRTNYNA PFKNKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARLTGTGFYWGQGTLVTVSAAKTTPPSVY PLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPS STWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVT CVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCR VNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVGWQWNGQ PAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO:214 (CDRs underlined)) and having CDR1 comprising or consisting of SEQ ID NO:P6; CDR2 comprising or consisting of SEQ ID NO:P7; and CDR3 comprising or consisting of SEQ ID NO:P8. In some embodiments, the SPP1 antibody comprises a light chain (LC) comprising a variable light (VL) chain domain comprising the amino acid sequence of any one of SEQ ID NOs: P1, P9, P17, P25, P33, P41, P49, P57, P65, P73, P81, P89, P97, P105, P113, P121, P129, P137, P145, P153, P161, P169, P177, and variants thereof with 1-5 single amino acid modifications (e.g., 1 or 2 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs; andAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017a heavy chain (HC) comprising a variable heavy (VH) chain domain comprising the amino acid sequence of any one of SEQ ID NOs: P5, P13, P21, P29, P37, P45, P53, P61 , P69, P77, P85, P93, P101, P109, P117, P125, P133, P141, P149, P157, P165, P173, P181 and variants thereof with 1-5 single amino acid modifications (e.g., 1 or 2 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs. In some embodiments, the SPP1 antibody is targeted to human SPP1 and / or is humanized. A variety of antibodies targeted to SPP1 can be useful in the compositions and methods of the present application. Additional SPP1 targeting sequences and antibodies are known in the art; for example, US 11,897,950; US 2023 / 0203193; WO 2011 / 021146; Fan, K. et al. (2011) European journal of pharmacology 657, 144–151; Hirano, Y., et al. (2016) Shock 46, 431–438; Yamamoto, N. et al. (2007) International immunopharmacology 7, 1460–1470; Yamamoto, N. et al. (2003) The Journal of clinical investigation 112, 181–188; Zhang, B. et al. (2014) Biochemical and biophysical research communications 452, 795–800; Shojaei, F. et al. (2012) Journal of experimental & clinical cancer research: CR 31, 26; Dai, J. et al. (2010) Cancer immunology, immunotherapy: CII 59, 355–366; and Kazanecki, C. C., et al. (2007) Journal of cellular biochemistry 102, 925–935. Other SPP1 antibodies include: Ab214055, Ab166709, Ab214050, Ab236213, Ab269441 (ThermoFisher); and hu1A12 (Absolute Antibody). IB. Chimeric Antigen Receptors A chimeric antigen receptor (CAR) refers to an artificial immune cell receptor that is engineered to recognize and bind to a surface antigen. A T cell that expresses a CAR polypeptide is referred to as a CAR T cell. CAR have the ability to redirect T-cell specificity and reactivity toward a selected target in a non-MHC-restricted manner. The non-MHC-restricted antigen recognition gives CAR T cells the ability to recognize an antigen independent of antigen processing, thereby bypassing a major mechanism of tumor escape. There are various generations of CARs, each of which contains different components. First generation CARs join an antibody-derived scFv to the CD3ζ intracellular signaling domain of the T cell receptor through a spacer region (also called a hinge domain) and a transmembrane domain. Second generation CARs incorporate an additional co-stimulatory domain (e.g., CD28,Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-0174-BB, or ICOS) to supply a co-stimulatory signal. Third generation CARs contain two co- stimulatory domains (e.g., a combination of CD27, CD28, 4-1BB, ICOS, or OX40) fused with the TCR CD3ζ chain. There can be a spacer between the co-stimulatory domain and the CD3ζ domain, but this is optional. A CAR is often fused to a signal peptide at the N-terminus for surface expression. In some cases the CAR can be co-expressed with a polypeptide that can serve as marker, for example a truncated EGFR receptor lacking signaling function or a truncated CD19 receptor lacking signaling function. (a) Extracellular Binding Domain The targeting domain (also called the extracellular binding domain) of useful CAR can be targeted to one or more antigen(s) present on the cell surface of a cancer cell. In some embodiments, the CAR comprise an scFv targeted to an antigen expressed on the surface of a cancer cell (e.g., a solid tumor). In some embodiments, the CAR include all or a portion of mature human IL13 or a variant thereof as a targeting domain (e.i., IL13Rα2 targeted CAR). In some embodiments, the CAR can comprise a targeting domain (e.g., an IL-13, a variant IL13, a chlorotoxin, a variant chlorotoxin or related toxin, a HER2 scFV, a PSCA scFv, a PSMA scFv, an EGFR scFv, CD70 scFv, etc.). In some embodiments, the extracellular binding domain comprises an scFv targeting a molecule expressed on the surface of a cancer cell, such as an antigen expressed on a solid tumor (e.g., HER2, PMSA, etc.). Thus, the extracellular binding domain of useful CAR can be targeted to, for example, IL13Rα2, MMP2, EGFR, HER2, PSCA, TAG72, PMSA, CD70, B7H3, etc. IL-13 In the case of a CAR targeted to IL13Rα2, the extracellular binding domain can comprise or consist of any one of: GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN (SEQ ID NO: 1); GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“YLK”; SEQ ID NO: 2);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“RLK”; SEQ ID NO: 3); GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“RL”; SEQ ID NO: 4); GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“YL”; SEQ ID NO: 5); GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFKEGRFN (“LK”; SEQ ID NO: 6); GPVPPSTALRRLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN (“R”; SEQ ID NO: 7); GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKILVAQFVKDLLLHLKKLFREGRFN (“L”; SEQ ID NO: 8); GPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFKEGRFN (“K”; SEQ ID NO: 9); GPVPPSTAVRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQR MLSGFCPHKVSAGQFSSLHVRDTRIEVAQFVKDLLNHLKELFTEGQFN (“C4”; SEQ ID NO: 10); GPVPPSTAARELIEELFNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTKRM LSGFCPHKVSAGQFPSLHVKKTRIEVAQFVKDLLIHLRKLFKEGQFN (“D7”; SEQ ID NO: 11); and GPVPPSTALRYLIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRM LSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN (“E”; SEQ ID NO: 12). In some embodiments, a IL-13 CAR can comprise or consist of the amino acid sequence of any one of SEQ ID NOs:149-178, or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the targeting domain (e.g., the IL13). Additional information, including IL-13 variants and IL-13Rα2 targeting sequences, as well as methods of making and using IL-13 CAR and immune cells expressing IL-13 CAR, are known in the art; e.g., WO 2008 / 146911, WO 2004 / 087758, WO 2021 / 154543, WO 2021 / 183960, WO 2022 / 212525, US 2023 / 0265147 A1. Chlorotoxin (CLTX) In the case of a CAR comprising a chlorotoxin (CLTX), variant thereof, or related toxin: the extracellular binding domain can comprise or consist of:Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017MCMPCFTTDHQMARKCDDCCGGKGRGKCYGPQCLCR (SEQ ID NO:14) or a variant thereof having 1-5 (e.g., 1 or 2) single amino acid modifications (e.g., substitutions) provided that the cysteine residues are not modified. In some embodiments, a CLTX CAR can comprise or consist of the amino acid sequence of any one of SEQ ID NOs:149-178, or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the targeting domain (e.g., the CLTX). Additional information, including CLTX variants and related toxins (such as GaTx2 & GaTx1, toxins from Leiurus quinquestriatus hebraeus, AaCtx, a toxin from Androctonus australis, etc.), sequences of the same, as well as methods of making and using CLTX CAR and immune cells expressing CLTX CAR, are known in the art; e.g., WO 2017 / 066481. Table 4: Examples of CAR Comprising Chlorotoxin Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 *SEQ ID NOs for sequence including signal sequence / SEQ ID NOs for sequence excluding signal sequence. EGFR In the case of CAR comprises an scFv targeted to an epidermal growth factor receptor (EGFR), a truncated EGFR (EGFRt), a variant of EGFR (e.g., epidermal growth factor receptor variant III; EGFRvIII), or the extracellular binding domain of EGFR. In some embodiments, an anti-EGFR scFv targets both wild-type EGFR and EGFRvIII. An EGFR scFv can comprise or consist of the amino acid sequence: DILMTQSPLSLPVSLGDQASISCRSSQNIVHNNGITYLEWYLQRPGQSPKLLIYKVSDRFSGVPD RFSGSGSGTDFTLKISRVEAEDLGIYYCFQGSHIPPTFGGGTKLEIKRAAGGGGSGGGGSGGG GSQVQLQQSGSEMARPGASVKLPCKASGDTFTSYWMHWVKQRHGHGPEWIGNIYPGSGGT NYAEKFKNKVTLTVDRSSRTVYMHLSRLTSEDSAVYYCTRSGGPYFFDYWGQGTTLTVSS (SEQ ID NO: 203; CDRs are underlines), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. An EGFR scFv can comprise or consist of the amino acid sequence: EIQLVQSGA EVKKPGESLR ISCKGSGFNI EDYYIHWVRQ MPGKGLEWMG RIDPENDETK YGPIFQGHVT ISADTSINTV YLQWSSLKAS DTAMYYCAFR GGVYWGQGTT VTVSSGGGGS GGGGSGGGGS GGGGSDVVMT QSPDSLAVSL GERATINC KSAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017SQSLLDSDGK TYLNWLQQKP GQPPKRLISL VSKLDSGVPD RFSGSGSGTD FTLTISSLQA EDVAVYYCWQ GTHFPGTFGG GTKVEIK (SEQ ID NO: 204; CDRs are underlines), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. An EGFR CAR can comprise or consist of the amino acid sequence: DILMTQSPLSLPVSLGDQASISCRSSQNIVHNNGITYLEWYLQRPGQSPKLLIYKVSDRFSGVPD RFSGSGSGTDFTLKISRVEAEDLGIYYCFQGSHIPPTFGGGTKLEIKRAAGGGGSGGGGSGGG GSQVQLQQSGSEMARPGASVKLPCKASGDTFTSYWMHWVKQRHGHGPEWIGNIYPGSGGT NYAEKFKNKVTLTVDRSSRTVYMHLSRLTSEDSAVYYCTRSGGPYFFDYWGQGTTLTVSSPK SCDKTHTCPPCPDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPG PTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGR DPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYD ALHMQALPPR (SEQ ID NO:197), or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) single amino acid modifications (e.g., amino acid substitutions); optionally, wherein the modifications are not in the CDRs; optionally, wherein the modifications are not in the targeting domain (e.g., the EGFR scFv). Additional EGFR targeting sequences (e.g., EGFR CDRs, EGFR variable domains (i.e., VL and VH), and EGFR scFvs) and EGFR targeted CAR, as well as methods of making and using the same, are known in the art; e.g., CDRs and sequences of cetuximab, panitumumab, necitumumab, nepidermin, nimotuzumab, amivantamab, HS-627, amelimumab, depatuxizumab, FmAb-2, GC-1118A, imgatuzumab, matuzumab, MVC-101, SCT-200, QL-1203, tomuzotuximab, zalutumumab, JMT-101, MCLA-158, QL-1105, SYN-004, MCLA-129, WBP- 297, AM-105, BH-2922, BMX-002, CMAB-017, DF-203, GB-263, JZB-29, SAH-EJ1, SFR- 9X0122, UBP-1215, ABX-901, MCLA-125, TXB-4BC2, 111-In-ch806, depatuxizumab mafodotin, DR-50201, DXL-1218, ENLS-1, FS-101, GI-3000, and described in WO 2011 / 056894; US 2014 / 0322275; US Pat. No.11,161,907. HER2 (also called ErbB2) In the case of CAR targeted to human epidermal growth factor receptor type 2 (HER2): the extracellular binding domain can comprise or consist of a HER2 scFv. In some embodiments, the HER2 scFv comprises or consists of the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017GSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGSTSGGGSGGGSGGGGSS EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADS VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 205), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. In some embodiments, the HER2 scFv comprises or consists of the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTGSTSGSGKPGSGEGSEV QLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVK GRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDVWGQGTLVTVSS (SEQ ID NO: 206; CDRs are underlined), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. In some embodiments, the HER2 scFv comprises or consists of the amino acid sequence: DIQMTQSP SSLSASVGDR VTITCRASQD VNTAVAWYQQ KPGKAPKLLI YSASFLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYYC QQHYTTPPTF GQGTKVEIKR TGSTSGSGKP GSGEGSEVQL VESGGGLVQP GGSLRLSCAA SGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF YAMDVWGQGT LVTVSS (SEQ ID NO:207) or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. In some embodiments, the HER2 scFv comprises or consists of the amino acid sequence: DIQMTQSP SSLSASVGDR VTITCRASQD VNTAVAWYQQ KPGKAPKLLI YSASFLESGV PSRFSGSRSG TDFTLTISSL QPEDFATYYC QQHYTTPPTF GQGTKVEIKR TGSTSGSGKP GSGEGSEVQL VESGGGLVQP GGSLRLSCAA SGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF VAMDVWGQGT LVTVSS (SEQ ID NO:208) or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017In some embodiments, the HER2 CAR comprises or consists of the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGSTSGGGSGGGSGGGGSS EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADS VKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSESKY GPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEV HNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKIYIWAPLAGTCGVLLLSLVITKRGRKK LLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGGGRVKFSRSADAPAYQQGQNQLYNE LNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGK GHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:180), or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) single amino acid modifications (e.g., amino acid substitutions); optionally, wherein the modifications are not in the CDRs; optionally, wherein the modifications are not in the targeting domain (e.g., the HER2 scFv). Thus, a HER2 CAR can include, from amino to carboxy terminus, an scFv (underlined) and spacer (not underlined) a CD8 transmembrane domain (underlined), a 4-1BB co-stimulatory domain (not underlined), a GGG linker (underlined) and a CD3zeta domain (not underlined). The spacer in this HER2 CAR of SEQ ID NO:180 is IgG4(S228P, L235E, N297Q). In some embodiments, a HER2 CAR can comprise or consist of the amino acid sequence of any one of SEQ ID NOs:179-196, or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the targeting domain (e.g., the HER2scFv). Additional HER2 targeting sequences (e.g., HER2 CDRs, HER2 variable domains (i.e., VL and VH), and HER2 scFvs) and HER2 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., 4D5, rastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, margetuximab, pertuzumab, disitamab vedotin, U-31402, ISU-104, SIB-001, 9F7- F11, EV-20Sap, U-31402, ARX-788, BAT-8001, HL-02, TAA-013, trastuzumab duocarmazine, A-166, AU-101, AU-105, BPX-603, ISB-1302, KN-026, MB-103, MRG-002, zanidatamab, zenocutuzumab, ACE-1702, ALTP-7, B-002, BAT-8001, BAT-1006, BAY-2701439, BTRC- 4017A, CAMH-2, cinrebafusp alfa, CT-0508, DP-303c, DX-126262, FS-102, FS-1502, GQ- 1001, HS-630, LCB-14, M-802, MBS-301, MT-5111, NJH-395, PF-06804103, SBT-6050, SENL-Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017006, SHRA-1201, SHRA-1811, TT-16, ZW-49; LZM-006; HER2Bi-armed ATC (Roger Williams Medical Center); WO 2017 / 079694; WO 2024 / 129964; WO 2023 / 196893; US 2024 / 0299543 A1; US Pat. No.11,161,907 (also called “ErbB2” and “4D5” therein); Liu X, Zhang N, Shi H. (2017) Oncotarget.8(37):62730-62741; Jiangang Sun, et. al. (2022) Journal of Inflammation Research, 15: 4061-4085. PSCA In the case of CAR targeted to prostate stem cell antigen (PSCA), the extracellular binding domain can comprise or consist of a PSCA scFv. For example, the scFv can comprise or consist of the amino acid sequence: DIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEV QLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKF QGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS (SEQ ID NO:209) or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. PSCAscFv-IgG4(HL-CH3)-CD4tm-41BB-Zeta DIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEV QLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKF QGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSESKYGPPCPPCPG GGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKMALIVLGG VAGLLLFIGLGIFFKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGGGRVKFS RSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDK MAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:198) or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5) single amino acid modifications (e.g., amino acid substitutions); optionally, wherein the modifications are not in the CDRs; optionally, wherein the modifications are not in the targeting domain (e.g., the PSCA scFv).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017PSCAscFv-Linker-CD4tm-41BB-Zeta DIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEV QLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKF QGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSGGGSSGGGSGMA LIVLGGVAGLLLFIGLGIFFKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGG GRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLY NELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO:199), or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) single amino acid modifications (e.g., amino acid substitutions); optionally, wherein the modifications are not in the CDRs; optionally, wherein the modifications are not in the targeting domain (e.g., the PSCA scFv). PSCAscFv-IgG4(S228P,L235E,N297Q)-CD4tm-41BB-Zeta DIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEV QLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKF QGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSESKYGPPCPPCPA PEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE QFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGKMALIVLGGVAGLLLFIGLGIFFKRGRKKLLYIFKQPF MRPVQTTQEEDGCSCRFPEEEEGGCELGGGRVKFSRSADAPAYQQGQNQLYNELNLGRREE YDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQ GLSTATKDTYDALHMQALPPR (SEQ ID NO:200), or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) single amino acid modifications (e.g., amino acid substitutions); optionally, wherein the modifications are not in the CDRs; optionally, wherein the modifications are not in the targeting domain (e.g., the PSCA scFv). Additional PSCA targeting sequences (e.g., PSCA CDRs, PSCA variable domains (i.e., VL and VH), and PSCA scFvs) and PSCA targeted CAR, as well as methods of making and using the same, are known in the art; e.g., WO 2017 / 062628; WO 2022 / 115421; US20240041921A1;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Morgenroth et al., (2007) Prostate 67(10):1121-1131 (scFv 7F5); Nejatollahi et al., (2013) J Oncology, article ID 839831 (scFv CS-II); and US 2009 / 0311181 A1. PSMA In the case of CAR targeted to prostate-specific membrane antigen (PSMA): the extracellular binding domain can comprise or consist of a PSMA scFv. For example, the scFv can comprise or consist of the amino acid sequence of: DIVMTQS HKFMSTSVGD RVSIICKASQ DVGTAVDWYQ QKPGQSPKLL IYWASTRHTG VPDRFTGSGS GTDFTLTITN VQSEDLADYF CQQYNSYPLT FGAGTMLDLK GGGGSGGGGS SGGGSEVQLQ QSGPELVKPG TSVRISCKTS GYTFTEYTIH WVKQSHGKSL EWIGNINPNN GGTTYNQKFE DKATLTVDKS SSTAYMELRS LTSEDSAVYY CAAGWNFDYW GQGTTLTVSS ASSG (SEQ ID NO: 210; CDRs are underlined), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the CDRs. Additional PSMA targeting sequences (e.g., PSMA CDRs, PSMA variable domains (i.e., VL and VH), and PSMA scFvs) and PSMA targeted CAR, as well as methods of making and using the same, are known in the art; CIK-CAR.PSMA (Formula Pharmaceuticals Inc), P-PSMA-101 (Poseida Therapeutics Inc), UniCAR-T-PSMA (GEMoaB Monoclonals GmbH), Parker et al., Protein Expr Purif 89(2):136-145 (2013), US 20110268656 (e.g., J591 ScFv); Frigerio et al, European J Cancer 49(9):2223-2232 (2013) (e.g., scFvD2B); WO 2006125481 (e.g., mAbs 3 / A12, 3 / E7, and 3 / F11 and (scFv A5 and D7). TAG72 In the case of CAR targeted to TAG72: the extracellular binding domain can comprise or consist of a TAG72 scFv. For example, the scFv can comprise or consist of: QVQLVQSGAEVVKPGASVKISCKASGYTFTDHAIHWVKQNPGQRLEWIGYFSPGNDDFKYSQ KFQGKATLTADTSASTAYVELSSLRSEDTAVYFCTRSLNMAYWGQGTLVTVSSGSTSGGGSG GGSGGGGSSDIVMSQSPDSLAVSLGERVTLNCKSSQSVLYSSNSKNYLAWYQQKPGQSPKLL IYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYPLSFGAGTKLELK (SEQ ID NO: 211; CDRs are underlined), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the CDRs.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017In some embodiments, a Tag72 CAR can comprise or consist of the amino acid sequence QVQLVQSGAEVVKPGASVKISCKASGYTFTDHAIHWVKQNPGQRLEWIGY FSPGNDDFKYSQKFQGKATLTADTSASTAYVELSSLRSEDTAVYFCTRSL NMAYWGQGTLVTVSS GSTS GGGSGGGSGGGGSS DIVMSQSPDSLAVS LGERVTLNCKSSQSVLYSSNSKNYLAWYQQKPGQSPKLLIYWASTRESGV PDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYPLSFGAGTKLELKE SKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGKMFWVLVVVGGVLACYSLLVTVA FIIFWVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELGG GRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKP RRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKD TYDALHMQALPPR (SEQ ID NO: 201), or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the CDRs. Additional TAG-72 targeting sequences (e.g., TAG72 CDRs, TAG72 variable domains (i.e., VL and VH), and TAG72 scFvs) and TAG72 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., WO 2020 / 028721. CD70 In the case of CAR targeted to CD70, the extracellular binding domain can comprise or consist of a CD70 binding domain (e.g., a CD70 scFv). For example, the scFv can comprise or consist of the amino acid sequence: QAVVTQEPS LTVSPGGTVT LTCGLKSGSV TSDNFPTWYQ QTPGQAPRLL IYNTNTRHSG VPDRFSGSIL GNKAALTITG AQADDEAEYF CALFISNPSV EFGGGTQLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL RLSCAAS GFT FSVYYMNWVR QAPGKGLEWV SDINNEGGTT YYADSVKGRF TISRDNSKNS LYLQMN SLRA EDTAVYYCAR DAGYSNHVPI FDSWGQGTLV TVSS (SEQ ID NO: 212; CDRs are underlined), or a variant thereof having 1-5 (e.g., 1, 2, 3, 4, or 5) single amino acid modifications (e.g., single amino acid substitutions); optionally, wherein the modifications are not in the CDRs. In some embodiments, a CD70 CAR comprises or consist of the amino acid sequence MARPHPWWLCVLGTLVGLSATPAPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHRKAAAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017QCDPCIPGVSFSPDHHTRPHCESCRHCNSGLLVRNCTITANAECACRNGWQCRDKECTECDP LPNPSLTARSSQALSPHPQPTHLPYVSEMLEARTAGHMQTLADFRQLPARTLSTHWPPQRSL CSSDFIRILVIFSGMFLVFTLAGALFLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFP EEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 202; called tr27-41BB-CD3zeta) or a variant thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) single amino acid modifications (e.g., substitutions); optionally, wherein the modifications are not in the CDRs. Additional CD70 targeting sequences (e.g., CD70 CDRs, CD70 variable domains (i.e., VL and VH), and CD70 scFvs) and CD70 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., Xiong, Q., et al. (2024) The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment. J Transl Med 22, 368; US 2023 / 0265147 A1; US 20230399412 A1; US20220411478A1; US20220347217A1; WO 2024 / 086841. B7H3 In the case of CAR targeted to B7 homolog 3 protein (B7H3), the extracellular binding domain can comprise or consist of a B7H3 scFv. For example, the scFv can comprise the CDRs of antibody MGA271. Many B7H3 targeting sequences (e.g., B7H3 CDRs, B7H3 variable domains (i.e., VL and VH), and B7H3 scFvs) and B7H3 targeted CAR, as well as methods of making and using the same, are known in the art; e.g., antibody MGA271 (Macrogenics); WO 2024 / 061306; WO 2024 / 226468; US20250136697A1; US20240245771A1; US20240252639A1. Commercial and Clinical CAR Additional CAR known in the art can be used in combination with the SPP1 antibodies described herein. This includes but is not limited to: Kymria™ (tisagenlecleucel), Yescart™ (axicabtagene ciloleucel), ALEXIS AIDT-2 EOC (Kiromic Biopharma Inc), CIK-CAR.PSMA (Formula Pharmaceuticals Inc), ADI-002 (Adicet Bio Inc), TSC-200 (TScan Therapeutics Inc), TSC-100 (TScan Therapeutics Inc), RB-H21 (Refuge Biotechnologies Inc), ADP-A2AFP (Adaptimmune Therapeutics plc), CT-0729 (Carisma Therapeutics), CT-1119 (Carisma Therapeutics), CCT-301-59 (EXUMA Biotech Corp), BOXR-889 (Unum Therapeutics Inc), meso-CAR-T+PD-78 (MirImmune LLC), MAGE-A10C796T (Adaptimmune Therapeutics plc), NKG2D-DARIC T-cells (Bluebird Bio Inc), AGENt-NY-ESO-1× (AgenTus Therapeutics Inc), MB-Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017105 (City of Hope Medical Center), P-MUC1C-101 (Poseida Therapeutics Inc), TT-16 (Baylor College of Medicine), ACTR-087 (Unum Therapeutics Inc), EGFR-806 (Seattle Children's Hospital), TAC01-ROR1 (Triumvira Immunologics Inc), CCT-301-38 (EXUMA Biotech Corp), MB-103 (Mustang Bio Inc), TAB-28z (OncoTab Inc), ET-1402 (Eureka Therapeutics Inc), ITI- 1000 (Duke University), CIDeCAR (Bellicum Pharmaceuticals Inc), MT-201 (Myeloid Therapeutics Inc), CT-0508 (Carisma Therapeutics), ADP-A2M4 (Adaptimmune Therapeutics plc), AMG-119 (Amgen Inc), iCasp9M28z T cells (Memorial Sloan-Kettering Cancer Center), P- PSMA-101 (Poseida Therapeutics Inc), ACE-1702 (Acepodia Inc), AIC-100 (Cornell University), PRGN-3005 (Precigen Inc), UniCAR-T-PSMA (GEMoaB Monoclonals GmbH), IMA-204 (MD Anderson Cancer Center), DSG3-CAART (University of Pennsylvania), LXF-821 (University of Pennsylvania), MOv19-BBz CAR T cells (University of Pennsylvania), Tn MUC-1 CAR-T (University of Pennsylvania), huMesoCART (University of Pennsylvania), IMA-203 (Immatics NV), IMA-202 (Immatics NV), XYP-317 (Xyphos Inc), CYAD-101 (Celyad Oncology), huMNC2- CAR44 T cells (Minerva Biotechnologies Corp), HER2Bi-armed ATC (Roger Williams Medical Center), and CYAD-200 series (Celdara Medical LLC), Lisocabtagene Maraleucel (liso-cel), FT596 (Fate Therapeutics), KTE-C19 (Kite Pharma Inc), KTE-X19 (Kite Pharma Inc), KITE-718 (Kite Pharma Inc), KITE-439 (Kite Pharma Inc), JCAR-024 (Fred Hutchinson Cancer Research Center), JCAR-023 (Juno Therapeutics Inc), BPX-201 (Bellicum Pharmaceuticals Inc), BPX-601 (Bellicum Pharmaceuticals Inc), BPX-603 (Bellicum Pharmaceuticals Inc), MCY-M11 (MaxCyte Inc), KUR-503 (Baylor College of Medicine), ICS-200 (University of Alabama at Birmingham), ADP-A2M4CD8 (Adaptimmune Therapeutics plc), GLYCAR (Baylor College of Medicine); and Jiangang Sun, et. al. (2022) Journal of Inflammation Research, 15: 4061-4085. (b) Transmembrane Domain The CAR polypeptides disclosed herein can contain a transmembrane domain, which can be a hydrophobic alpha helix that spans the membrane. As used herein, a transmembrane domain refers to any protein structure that is thermodynamically stable in a cell membrane, preferably a eukaryotic cell membrane. The transmembrane domain of the CAR constructs used in the Examples has CD4 transmembrane domain having the sequence: MALIVLGGVAGLLLFIGLGIFF (SEQ ID NO: 18) or a CD28 TM having the sequence MFWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO:17). Other transmembrane domains can be used including those shown below.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Table 1: Examples of Transmembrane Domains (c) Spacer Domain The CAR or polypeptide described herein can include a spacer domain located between the targeting domain and the transmembrane domain. The spacer region can function to provide flexibility to the CAR, or domains thereof, or to prevent steric hindrance of the CAR, or domains thereof. A variety of different spacers can be used. Some of them include at least portion of a human Fc region, for example a hinge portion of a human Fc region or a CH3 domain or variants thereof. Table 2 below provides various spacer domains that can be used in the CARs described herein.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Table 2: Examples of Spacer Domains Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 Some spacer domains include all or part of an immunoglobulin (e.g., IgG1, IgG2, IgG3, IgG4) hinge region, i.e., the sequence that falls between the CH1 and CH2 domains of an immunoglobulin, e.g., an IgG4 Fc hinge or a CD8 hinge. Some spacer domains include an immunoglobulin CH3 domain (called CH3 or ΔCH2) or both a CH3 domain and a CH2 domain. The immunoglobulin derived sequences can include one or more amino acid modifications, for example, 1, 2, 3, 4 or 5 substitutions, e.g., substitutions that reduce off-target binding. The spacer domain can also comprise an IgG4 hinge region having the sequence ESKYGPPCPSCP (SEQ ID NO: 26) or ESKYGPPCPPCP (SEQ ID NO: 25). The hinge / linger region can also comprise the sequence ESKYGPPCPPCP (SEQ ID NO: 25) followed by the linker sequence GGGSSGGGSG (SEQ ID NO: 24) followed by IgG4 CH3 sequence: GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 34). Thus, the spacer domain can comprise the sequence: ESKYGPPCPPCPGGGSSGGGSGGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSLGK (SEQ ID NO: 31). In some cases, the spacer has 1, 2, 3, 4, or 5 single amino acid changes (e.g., conservative changes) compared to SEQ ID NO: 31. In some cases, the IgG4 Fc hinge / linker region that is mutated at two positions (L235E; N297Q) in a manner that reduces binding by Fc receptors (FcRs). (d) Intracellular Signaling Domains Any of the CAR constructs described herein contain one or more intracellular signaling domains (e.g., CD3ζ, and optionally one or more co-stimulatory domains), which are the functional end of the receptor. Following antigen recognition, receptors cluster and a signal is transmitted to the cell.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017CD3ζ is the cytoplasmic signaling domain of the T cell receptor complex. CD3ζ contains three immunoreceptor tyrosine-based activation motifs (ITAMs), which transmit an activation signal to the T cell after the T cell is engaged with a cognate antigen. In some cases, CD3ζ provides a primary T cell activation signal but not a fully competent activation signal, which requires a co- stimulatory signal. Accordingly, in some examples, the CAR polypeptides disclosed herein may further comprise one or more co-stimulatory signaling domains in addition to CD3ζ. For example, the co- stimulatory domain CD28 and / or 4-1BB can be used to transmit a proliferative / survival signal together with the primary signaling mediated by CD3ζ. The co-stimulatory domain(s) are located between the transmembrane domain and the CD3ζ signaling domain. Table 3 includes examples of suitable co-stimulatory domains together with the sequence of the CD3ζ signaling domain. Table 3: CD3ζ Domain and Examples of Co-stimulatory Domains Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017 In some examples, the CD3ζ signaling domain comprises an amino acid sequence that is at least 90%, at least 95%, at least 98% identical to SEQ ID NO: 35. In such instances, the CD3ζ signaling domain has 1, 2, 3, 4, or 5 amino acid changes (preferably conservative substitutions) compared to SEQ ID NO: 35. In other examples, the CD3ζ signaling domain is SEQ ID NO: 35.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017In various embodiments: the co-stimulatory domain is selected from the group consisting of: a co-stimulatory domain depicted in Table 3 or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a CD28 co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications, a 4-1BB co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications and an OX40 co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications. In certain embodiments, a 4-1BB co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications is present in the CAR polypeptides described herein. In some embodiments, there are two co-stimulatory domains, for example, a CD28 co- stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions) and a 4-1BB co-stimulatory domain or a variant thereof having 1-5 (e.g., 1 or 2) amino acid modifications (e.g., substitutions). In various embodiments the 1-5 (e.g., 1 or 2) amino acid modification are substitutions. In various embodiments, the co-stimulatory domain is amino terminal to the CD3ζ signaling domain and a short linker consisting of 2 – 10, e.g., 3 amino acids (e.g., GGG) can be positioned between the co-stimulatory domain and the CD3ζ signaling domain. In some cases, the CAR can be produced using a vector in which the CAR open reading frame is followed by a T2A ribosome skip sequence and a truncated EGFR (EGFRt), which lacks the cytoplasmic signaling tail, or a truncated CD19R (also called CD19t). In this arrangement, co- expression of EGFRt or CD19t provides an inert, non-immunogenic surface marker that allows for accurate measurement of gene modified cells, and enables positive selection of gene- modified cells, as well as efficient cell tracking of the therapeutic T cells in vivo following adoptive transfer. Efficiently controlling proliferation to avoid cytokine storm and off-target toxicity is an important hurdle for the success of T cell immunotherapy. The EGFRt or the CD19t incorporated in the CAR lentiviral vector can act as suicide gene to ablate the CAR+ T cells in cases of treatment-related toxicity. The CD3ζ signaling domain can be followed by a ribosomal skip sequence (e.g., LEGGGEGRGSLLTCGDVEENPGPR; SEQ ID NO: 45) and a truncated EGFR having a sequence that is at least 90%, at least 95%, at least 98% identical to or identical to: LVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFT HTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSL GLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017GCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGR GPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEG CPTNGPKIPSIATGMVGALLLLLVVALGIGLFM (SEQ ID NO: 46). In some cases, the truncated EGFR has 1, 2, 3, 4 of 5 amino acid changes (preferably conservative) compared to SEQ ID NO: 46. Alternatively the CD3ζ signaling domain can be followed by a ribosomal skip sequence (e.g., LEGGGEGRGSLLTCGDVEENPGPR; SEQ ID NO: 45) and a truncated CD19R (also called CD19t) having a sequence that is at least 90%, at least 95%, at least 98% identical to or identical to: MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLK LSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWN VSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCVPPRDSLNQSLSQD LTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLP RATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHL QRALVLRRKR (SEQ ID NO: 47). The CAR described herein can be produced by any means known in the art, though preferably it is produced using recombinant DNA techniques. Nucleic acids encoding the several regions of the chimeric receptor can be prepared and assembled into a complete coding sequence by standard techniques of molecular cloning known in the art (genomic library screening, overlapping PCR, primer-assisted ligation, site-directed mutagenesis, etc.) as is convenient. The resulting coding region is preferably inserted into an expression vector and used to transform a suitable expression host cell line, preferably a T lymphocyte, and most preferably an autologous T lymphocyte. Various T cell subsets isolated from the patient can be transduced with a vector for CAR or polypeptide expression. Central memory T cells are one useful T cell subset. Central memory T cell can be isolated from peripheral blood mononuclear cells (PBMC) by selecting for CD45RO+ / CD62L+ cells, using, for example, the CliniMACS® device to immunomagnetically select cells expressing the desired receptors. The cells enriched for central memory T cells can be activated with anti-CD3 / CD28, transduced with, for example, a lentiviral vector that directs the expression of a CAR or as well as a non-immunogenic surface marker for in vivo detection, ablation, and potential ex vivo selection. The activated / genetically modified central memory TAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017cells can be expanded in vitro with IL-2 / IL-15 and then cryopreserved. Additional methods of preparing CAR T cells can be found in PCT / US2016 / 043392. Methods for preparing useful T cell populations are described in, for example, WO 2017 / 015490 and WO 2018 / 102761. In some cases, it may be useful to use natural killer (NK) cells, e.g., allogenic NK cells derived from peripheral blood or cord blood. In other cases, NK cells can be derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). In some embodiments, described herein is a composition comprising the iPSC-derived CAR T cells or CAR NK cells. In some embodiments, a composition comprising iPSC-derived CAR T cells or CAR NK cells has enhanced therapeutic properties. In some embodiments, the iPSC- derived CAR T cells or CAR NK cells demonstrate enhanced functional activity including potent cytokine production, cytotoxicity and cytostatic inhibition of tumor growth, e.g., as activity that reduces the amount of tumor load. The CAR can be transiently expressed in a T cell population by an mRNA encoding the CAR. The mRNA can be introduced into the T cells by electroporation (Wiesinger et al.2019 Cancers (Basel) 11:1198). In some embodiments, a composition comprising the CAR T cells comprise one or more of helper T cells, cytotoxic T cells, memory T cells, naïve T cells, regulatory T cells, natural killer T cells, or combinations thereof. II. Treatment of Patients Aspects of the present disclosure provide methods for treating a subject with cancer (e.g., gliomas, such as glioblastoma, and solid tumors, including metastases thereof) by administering an antibody targeted to human SPP1 and a population of immune cells, e.g., IL13 CAR T cells, HER2 CAR T cells, PSMA CAR T cells, and PSCA CAR T cells. The cancer can include cells that express IL13Rα, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA, and PSMA. (a) Subjects The terms “subject” and “patient” are used interchangeably throughout. The subject to be treated by the methods described can be a human subject having a cancer, such as a cancer comprising cells that express any one of IL13Rα2 MMP2, EGFR / EGFRvIII, TAG72, B7H3,Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017CD70, HER2, PSCA, and PSMA. In some embodiments, a subject has a glioma, a, glioblastoma, a solid tumor, and / or a metastasis of any thereof. (b) Administration An effective amount of a therapy (e.g., an SPP1 antibody described herein and / or immune cells expressing a CAR described herein) can be administered to a subject (e.g., a human) in need of the treatment via any suitable route (e.g., administered locally or systemically to a subject). Suitable modes of administration include injection, infusion, instillation, or ingestion. Injection includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intradermal, intraperitoneal, subcutaneous injection, and infusion. In some embodiments, an SPP1 antibody described herein can administered together with a population of immune cells expressing a CAR (e.g., CAR T cells, CAR NK cells, CAR M cells) targeted to, for example, human IL-13Rα2, MMP2, EGFR / EGFRvIII, TAG72, B7H3, CD70, HER2, PSCA or PSMA. In some embodiments, the SPP1 antibody is administered prior to administration of the CAR (e.g., CAR T cells). In some embodiments, the administration of the SSP1 antibody can precede administration of the CAR by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or longer. In some embodiments, the SPP1 antibody is administered several times prior to the administration of the CAR and the second or subsequent administration of the SPP1 antibody can be at any point prior to, coincident with, or subsequent to administration of the CAR (e.g., CAR T cells). For example, the SPP1 antibody can be administered to a subject in need thereof (e.g., suffering from a cancer) two or three times prior to the administration of the CAR and a subsequent administration of the SPP1 antibody can be administered coincident with the administration of the CAR (e.g., population of CAR immune cells, e.g., CAR T cells). An effective amount refers to the amount of each active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of treatment, the nature of concurrent therapy, if any, the specific route of administration and like factors. A therapeutic effect on the subject can be determined as the amelioration of one symptom associated with the condition being treated or a reduction of size or number of cancer cells in the subject (e.g., 1%, 2%, 3%, 4%, or 5% decrease in size or number of cancer cells).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Methods GBM / HGG tumor samples acquisition and processing Baseline tumor tissue samples were obtained from 41 patients with recurrent / refractory malignant glioma participating in a Phase I study (IRB #13384) on cellular immunotherapy using central memory-enriched IL13Rα2-targeting Chimeric Antigen Receptor (CAR) T cells. Tumor resection material was collected through the COH Department of Pathology according to the clinical protocol. GBM / HGGs library preparation and single-cell sequencing Single-cell sequencing of cryopreserved freshly dispersed tumor samples from 41 individuals was carried out using the 10x Chromium platform. For Batch 1, patient PBMC’s exomes were collected via Illumina exome panel and sequenced at 20M read pairs per patient for sample deconvolution. For batches 2-6 and batches 42-1, 42-2, 43-1, 43-2, 44-2, 45, 46, and 47, BioLegend Total Seq-C hashtag antibodies were used to allow sample deconvolution after pooled processing, with barcoded samples sorted at equal proportions into a single collection tube. Samples in the remaining batches were sequenced without pooling.60,000 cells were loaded to a single Gel Bead-in-Emulsion (GEM) reaction onto the Chromium instrument. ScRNA-seq library preparation was performed according to manufacturer protocols and sequenced on Illumina iSeq100 for cell count validation and NovaSeq6000 at the recommended depth. Sequence data were processed using 10x Genomics Cell Ranger V5.0 and Ensemble 98. GBM / HGG tumor single-cell data processing and analysis Single-cell sequencing data were analyzed using Seurat v5. CellRanger objects for each batch were imported to create a Seurat object for each of the 37 batches. For Batch 1, sample identities were deconvoluted, and multiplets were identified using Demuxlet. Exome sequencing FASTQ reads were chunked to 40M reads, aligned to GRCh38 using BWA, and processed with samtools (v1.10) fixmates and samtools sort (v1.10). Individual chunks were merged, and PCR and optical duplicates were marked with samtools. Genotypes were called with DeepVariantAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017(github.com / google / deepvariant). For the batches with hash-antibodies, demultiplexing was done using the HTODemux() function of Seurat. The single-cell data were filtered to retain singlets with >500 unique RNA features detected, >1,000 RNA feature counts, and <10% of reads mapping to mitochondrial genes. After demultiplexing and quality filtering, we filtered the data for ambient RNA contamination using SoupX v1.6.2. In the batches sequenced without multiplexing, possible doublets were identified using DoubletFinder v2.0.3. Gene expression data were normalized with SCT, and samples were integrated using rPCA. The number of significant principal components (PCs) to be included in dimensionality reduction and unsupervised clustering was determined by calculating the difference between the proportion of variation associated with each PC and their subsequent PC and selecting the last point where the difference is more than 0.1%. Uniform Manifold Approximation and Projection (UMAP) was used for dimensionality reduction and 2D visualization of cell clusters. The scRNA-seq data were analyzed for copy number alterations using the R package InferCNV v1.20.0 (github.com / broadinstitute / inferCNV) with the following parameters: HMM_type = “i3, hclust_method = ‘ward.D2’, sd_amplifier = 3, noise_logistic = T, tumor_subcluster_partition_method = ‘random_trees’. Highly expressed marker features for each cluster were identified using the presto (v1.0.0) implementation of the Wilcoxon rank test (github.com / immunogenomics / presto). Clusters were annotated based on cell type marker expression. Two clusters that did not express reasonable levels of any cell type markers and consisted mostly of cells from single individuals were excluded from downstream analyses. For the differential expression analysis between groups, we employed the Seurat implementation of the Wilcoxon rank sum test. We tested for the statistical significance of differences in cell type abundance between groups using the R package scProportionTest. Ligand-receptor interaction analysis was carried out using CellChat v2.1.1 leveraging the CellChatDB human database (v1.0.0), which contains 1,939 validated molecular interactions, including 61.8% of paracrine / autocrine signaling interactions, 21.7% of extracellular matrix (ECM)-receptor interactions and 16.5% of cell-cell contact interactions. Expression data were preprocessed for the cell-cell communication analysis by identifying over-expressed ligands or receptors in one group and then identifying over-expressed ligand-receptor interactions. Then, gene expression data were projected onto the protein-protein interaction network using the function projectData(). Next, communication probabilities were computed using computeCommunProb(), and the results were filtered to retain instances with a minimum of ten cells in each group. Cell-cell communication was inferred at a pathway level by summarizing theAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017communication probabilities of all ligands-receptor interactions associated with each signaling pathway using computeCommunProbPathway(), and the aggregated communication network was calculated by counting the number of links and summarizing the communication probability using aggregateNet(). To test for the effects of cell type abundance and gene expression levels on overall survival, we employed Cox proportional-hazards model using the coxph() function of the R package survival v 3.5-5 (github.com / therneau / survival). We used the escape v 2.1.3 to calculate enrichment scores for KEGG, REACTOME, BIOCARTA, and HALLMARK gene sets for each single cell. The enrichment calculation was carried out using the enrichIt() function, which utilizes the GSVA R package (v1.53.22) and the Poisson distribution for RNA. JAK1KO / WT tumor library preparation and single-cell sequencing The mouse scRNA-seq library preparation was performed according to the manufacturer protocols and sequenced on Illumina iSeq100 for cell count validation and NovaSeq6000 at the recommended depth. JAK1KO / WT tumor single-cell data processing and analysis Raw base call files of scRNA-seq data were analyzed using CellRanger (version 5.0). The “mkfastq” command was used to generate FASTQ files and the “count” command was used to generate raw gene-barcode matrices aligned to the 10X Genomics GRCm38 reference genome (mm10). The data from all samples were combined in R (4.0.4) using the Read10X() function from the Seurat package (v4.0.3) and an aggregate Seurat object was generated. Filtering was conducted by retaining cells that had unique molecular identifiers (UMIs) greater than 400, expressed 200 and 9000 genes inclusive, and had mitochondrial content less than 15 percent. No sample batch correction was performed. Data were normalized using the “LogNormalize” method and using a scale factor of 10,000. Using Seurat’s ScaleData() function and “vars.to.regress” option UMI’s and percent mitochondrial content were used to regress out unwanted sources of variation. The number of variably expressed genes were calculated using the following criteria: normalized expression between 0.125 and 3, and a quantile-normalized variance exceeding 0.5. To reduce dimensionality of this dataset, the resulting variably expressed genes were summarized by principle component analysis (PCA), and the first 20 principle components further summarized using Uniform Manifold Approximation and Projection (UMAP) dimensionality reduction. Doublets were assessed using the DoubletFinder (version 2.0.2) algorithm and few (<10%) doublets were observed outside of the cell population. Clustering was conducted with the FindClusters() function using 20 PCA components and aAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017resolution parameter set to 0.3. Cell cycle analysis was conducted using the CellCycleScoring() in Seurat package with a list of cell cycle markers from Aviv Regev et al’s study. Differentially expressed genes among clusters and treatments were identified with logFC greater than 0.25 (adjusted p < 0.05) as determined in Wilcoxon rank-sum test from Seurat. The markers for different cell types were retrieved from CellMarker database, which is a manually curated resource of cell markers in human and mouse. The pathway analysis was done using Gene Ontology and canonical pathways in enrichr, with adjusted P < 0.05 as the cutoff for statistically differential pathways. Cell–cell interactions based on the expression of known ligand–receptor pairs in different cell types were inferred using CellChatDB (v1.0.0). The total counts of interactions and interaction strengths were calculated using the compareInteractions function in CellChat. The differential edge list was passed through CircosDiff (a wrapper around the R package ‘circlize’) and netVisual_chord_gene in CellChat to filter receptor ligand edges and generate Circos plots. Integrated analysis of GBM / HGG and JAK1KO / WT tumors scRNA-seq data Immune and stromal compartments of the GBM and JAK1KO / WT scRNA-seq data were jointly integrated using rPCA as described above. Cytometry by Time-of-flight analysis (CyTOF) YUMM JAK1 / KO and WT tumor cells (0.3×106) were implanted into the flanks of C57BL / 6 mice. On day 8 post-inoculation, tumors were harvested from mice at predefined treatment time points. Tumors were digested using the Tumor Dissociation Kit Mouse (Miltenyi Biotec). Immune cells were isolated using the CD45+ isolation kit (EasySepTM Mouse CD45 Positive Selection Kit, STEMCELL Technologies). A panel of 35 immune markers was used for analysis. Samples were analyzed using the Fluidigm Helios Mass Cytometry System at the UCLA Flow Cytometry core. Manual gating was performed using FlowJo software (version 10.4.2) to identify cells, singlets, and viable CD45+ populations. Data files were analyzed using OMIQ software. Cluster median data were normalized, and a threshold of >0.5 was used to define positive immune markers for cluster identification and annotation. Murine RNA Isolation and RNA-seq analysis For in vitro experiments, melanoma cell lines were seeded of 1.5 × 105 cells per 6-well plate for treatment. After 24 hours, the culture media were replaced with fresh media containing IFNγ (BD Pharmingen, catalog no.554616) or supernatant of mIL13Rα2 CAR T cells with YUMM2.1 WT tumors. Cells were harvested 8 hours after treatment. The cell pellets were lysed in TRIzol reagent (Invitrogen, catalog no.15596018) and stored at −80°C until RNA extraction.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017For in vivo experiments, engrafted tumors treated with or without mIL13, mIL13-ISG15, or mIL13- mutISG15 CAR T cells were harvested and dissociated into single cells and stored at - 80°C prior to RNA extraction. Total RNA was extracted from mouse tissues using TRIzolTM Reagent (Life Technologies) for transcriptome analyses. RNA integrity, purity, and concentration were evaluated using an Agilent 2100 Bioanalyzer (Agilent Technologies). Nanodrop and Qubit 3.0. RNA-seq libraries were constructed using KAPA mRNA HyperPrep Kit. RNA-seq was performed in the Illumina HiSeq2000 System using 51 bp single-end sequencing. High-quality reads were obtained by trimming the raw reads using fastp (v0.23.3) and by carrying out FastQC (v0.11.9) for the quality control assessment. The clean reads were aligned to the mouse reference genome GRCm38 with HISAT-STRINGTIE analytic pipeline (HISAT2 v2.1.0; Stringtie v1.3.4). The DESeq2 (v.1.26.0) framework was adopted for differential expression analysis. Maintenance of mouse cell lines The YUMM sublines (YUMM WT and YUMM JAK1 / KO) as well as the MC38 cell lines (MC38 WT and MC38 JAK1 / KO) were graciously provided by the Antoni Ribas laboratory, located within the comprehensive cancer center at UCLA. Both the YUMM and MC38 sublines were cultured at 37°C with 5% CO2 in DMEM (Invitrogen), supplemented with 10% FBS, 100 U / mL penicillin, 100 μg / mL streptomycin, and 0.25 μg / mL amphotericin B. Regular screenings ensured the absence of Mycoplasma contamination, utilizing the MycoAlert Mycoplasma Detection Kit (Lonza), and authentication tests were periodically conducted. For in vivo experiments, early-passage cell lines (less than 10 passages) were utilized. In vivo studies All experimental procedures involving mice were conducted in accordance with the protocols approved by the City of Hope IACUC. For the subcutaneous models, 3 × 106YUMM WT and JAK1 / KO cells suspended in PBS were injected into the left flanks of 8-10-week-old C57BL / 6J mice. After allowing 8 days for tumor establishment, 0.4 × 106mIL13Rα2 CAR T cells were administered directly into the tumors. Similarly, in the MC38 model, 1 × 106MC38 WT and JAK1 / KO cells were injected into the mice, followed by the same treatment after 8 days. For systemic administration, 5 × 106mIL13Rα2 CAR T cells were infused via the tail vein on day 8 post-tumor inoculation. Tumor volumes were regularly measured using calipers. In the orthotopic model, 1 × 105tumor cells were stereotactically implanted intracranially into the right forebrain of mice. Successful engraftment was confirmed by bioluminescence imaging the day before injecting the CAR T cells. Mice were grouped based on bioluminescence intensity. Fourteen days post-tumor implantation, mice received an intracranial administration ofAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-0171 × 106mIL13Rα2 CAR T cells. Tumor progression was monitored using SPECTRAL LagoX and analyzed with Aura software. Survival outcomes were charted using GraphPad Prism Software (v10). For combination therapies in flank models, the pretreatment group was administered three doses every other day before CAR T cell therapy and received three additional doses afterward. The simultaneous treatment group was given an initial dose of anti-OPN antibody (bioXcell Clone: 100D3) on the day of CAR T cell therapy, followed by five more doses to ensure parity in antibody delivery across groups, all given intraperitoneally (IP). In the orthotopic model, the combination group received three doses of anti-SPP1 antibody (clone MPIIIB10) prior to the CAR T cell therapy on day 8, continuing with five subsequent doses IP. All mice were continually observed by the Center for Comparative Medicine at City of Hope for signs of tumor progression and overall survival, with euthanasia applied in adherence to the American Veterinary Medical Association Guidelines. Biostatistics Statistical significance in the in vivo studies was assessed utilizing either a Student t-test for two groups or a one-way ANOVA with Bonferroni correction for three or more groups. Survival analysis was represented via Kaplan-Meier survival curves, with statistical significance determined by the log-rank (Mantel-Cox) test. All statistical analyses were conducted using GraphPad Prism software (v10). Significance levels were denoted as follows: *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. YUMM and MC38 sublines expansion Mouse tumor cells expanded in vitro were stained with an unconjugated goat anti-mouse IL13Rα2 (R&D Systems) followed by secondary donkey anti-goat NL637 (R&D Systems). Live murine CAR T cells were stained with CD3 (eBioscience) and CD19 (BD Biosciences) as a surrogate to detect the CAR. ICAM-1 engineering of the tumor cells The plasmid containing the ICAM-1 gene and the packaging plasmids were provided by VectorBuilder. The lentiviral backbone was used for the construction of the expression vector. The cells were then incubated with the lentivirus following the protocol provided by Vectorbuilder. Neomycin (Geneticin) was used for positive selection of the transduced cells. The overexpression of ICAM-1 was confirmed using flow cytometry analysis. In vitro verification of YUMM and MC38 sublines To fully characterize the differential IFN-induced gene expression, the engineered YUMM JAK1 / KO and YUMM-WT as well as MC38 JAK1 / KO and MC38 WT were exposed toAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017supernatants derived from CAR T cell mediated cytotoxicity with matched YUMM and MC38 WT tumors. The cells, subsequently, were sent to bulk RNA-sequencing for transcriptional analysis. Murine CAR T cells The murine IL13Rα2 CAR was engineered within an MSCV retroviral backbone (Addgene), comprising the murine IL13 extracellular domain, murine CD8 hinge, murine CD8 transmembrane domain, and intracellular murine 4-1BB costimulatory and murine CD3ζ signaling domains. A truncated murine CD19 was inserted downstream via a T2A ribosomal skip as a transduction marker. The resulting plasmid was transfected into PlatE cells (courtesy of Dr. Zuoming Sun’s lab) using Fugene (Promega). After 48 hours, the supernatant was harvested and filtered through a 0.2-μm filter, then aliquoted and stored frozen until transduction. Murine T cells were isolated from spleens of naïve C57BL / 6J mice or using the EasySep Mouse T cell Isolation Kit (STEMCELL Technologies) and activated with Dynabead Mouse T-Activator CD3 / CD28 beads (Gibco) at a 1:1 ratio. Transduction of T cells occurred on RetroNectin-coated plates (Takara Bio) using retrovirus-containing supernatants (as described above). Cells were then expanded for 4 days in RPMI 1640 (Lonza) supplemented with 10% FBS (Hyclone Laboratories), 55 mmol / L 2-mercaptoethanol (Gibco), 50 U / mL recombinant human IL2 (Novartis), and 10 ng / mL recombinant murine IL7 (PeproTech). Prior to in vitro and in vivo experiments, beads were magnetically separated from T cells and CAR expression was assessed via flow cytometry. In vitro cytotoxicity using Xcelligence assay The assay was performed following a standardized protocol. On Day 1, the plate map was set up in the Xcelligence software based on the experimental design. Target cells were dissociated using trypsin or scraped to remove enzymes, resuspended in assay media, and passed through a 40 μm cell strainer to eliminate clumps. Cell counts were determined using the Muse Cell Analyzer, and cells were resuspended at the desired concentration. A total of 50 μL of assay media was added to each well of the E-plate, and background signal was recorded on the Xcelligence instrument, ensuring no bubbles were present. The plate was then removed, and 100 μL of the target cell suspension was added to each well. Cells were allowed to settle for 45 minutes at room temperature before placing the plate back on the instrument to minimize edge effects and ensure accurate readings. Target cells were cultured for 24 hours at 37°C in a humidified incubator with 5% CO!. On Day 2, effector cells were prepared at a concentration of 1.0 × 10⁶ cells / mL for each cell line, followed by serial dilutions to achieve the desired effector- to-target (E:T) ratio. The Xcelligence experiment was paused, and 100 μL of the prepared effector cell suspension was added to each well in a tissue culture hood. Cells were allowed toAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017settle for 45 minutes at room temperature before resuming the experiment on the Xcelligence instrument. Immunofluorescence staining Immunofluorescence was done on 5 µm-thick sections of FFPE (formalin-fixed paraffin- embedded) specimens placed on positively charged glass slides. The slides were deparaffinized in xylene, rehydrated in an ethanol gradient, and underwent antigen retrieval (10 min, 110-116 o C) in citrate-based antigen unmasking solution (#H-3300, Vector Laboratories) using a pressure cooker. The slides were then washed and incubated with carbohydrate-free blocking solution (#SP- 5040, Vector Laboratories) prior to staining. The slides were then incubated with anti- COL1A1 antibody (E3E1X, Cell Signaling, #66948), anti-SPP1 (#AF1433, R&D) and anti-CD68 (EPR20545, Abcam, #ab213363) overnight at 4 °C, followed by incubation with donkey anti- mouse Alexa Fluor 555 (#A-31570), donkey anti-goat Alexa Fluor 488 (#A-11055), donkey anti- rabbit Alexa Fluor 647 (#A-31573) and Hoechst 33342 (#H3570, Thermofisher Scientific) for 1 hour (RT). The slides were then coverslipped and scanned using a Zeiss LSM880 confocal microscope. Murine tissues were incubated with anti-COL1A1 antibody (E8F4L, Cell Signaling, #72026), anti-SPP1 (#AF808, R&D) and anti-CD68 (FA-11, Invitrogen, #14-0681-82), followed by incubation with donkey anti-rat Alexa Fluor 594 (#A-21209), donkey anti-mouse Alexa Fluor 647 (#A-31571), donkey ant-rabbit Alexa Fluor 647 (#A-31573) and Hoechst 33342 (#H3570). Cell Proliferation and Activation Human IL13Ra2 CAR T cells (25000) were incubated with 1 µM CFSE at room temperature for 20 min. After washes three times with PBS, the CFSE-stained CAR T cells were added in 96-well plate coated with 2.5 µg / mL anti-CD3 antibody (clone: OKT3). The presence and absence of 10 µg / mL human recombinant SPP1, as well as the presence and absence of 10 µg / mL anti-SPP1 antibody (clone: MPIIIB10) was tested, as indicated in figures (e.g., FIGS. 31A-31B). After 3 days of incubation, cells were collected and subjected to flow cytometry to measure cell proliferation (measured by CFSE) and activation (measured by CD69 and CD25). Human IL13Ra2 CAR T cells (25000) were incubated with 1 µM CFSE at room temperature for 20 min. After washes three times with PBS, the CFSE-stained CAR T cells were added in 96-well plate coated with different titrations of human IL13Ra2-Fc (0, 31, 62.5, 125, 250, 500 µg / mL) or 2.5 µg / mL anti-CD3 antibody (clone: OKT3) and in the presence and absence of 10 µg / mL human recombinant SPP1. After 3 days of incubation, cells were collected and subjected to flow cytometry to measure cell proliferation (measured by CFSE) and activation (measured by CD69 and 41BB).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Described below is single-cell RNA sequencing (scRNA-seq) analysis of tumors from 41 glioma patients undergoing IL13Rα2-targeted CAR T cell therapy. This study identified elevated suppressive SPP-1 signatures in macrophages from patients who were resistant to treatment. Also described is integrative scRNA-seq analysis of glioblastoma tumor samples and an interferon-signaling deficient syngeneic mouse model—both resistant to CAR T therapy that demonstrate the role of congruent suppressive pathways in mediating resistance to CAR T cells. Also described is a study showing that SPP1 blockade with an anti-SPP1 antibody prior to CAR T cell therapy abrogates the suppressive effects and substantially prolongs survival in syngeneic resistance models to CAR T cell therapies. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Example 1: Suppressive tumor microenvironment limits response to CAR T therapy in high-grade glioma Recognizing the unique challenges posed by solid tumors to CAR T cell therapy, a series of experiments was performed to identify dominant networks within GBM / HGG associated with patient outcomes to adoptive T cell therapy. To elucidate the resistance features within gliomas in response to CAR T cells, we performed scRNA-seq on freshly dissociated pretreatment tumors obtained from 41 glioma patients undergoing IL13Ra2-targeted CAR T cell therapy (FIG 1A). Glioma tumors were characterized demographically and stratified based on CD3+ T cell infiltration (CD3 low / CD3 high) and therapeutic outcome to CAR T cells (progressive diseases (PD) in comparison to complete response, partial response or stable disease (CR / PR / SD)) (FIG 1B). Accordingly, patients were stratified based on treatment outcome, comparing patients who progressed through therapy (progressive disease, PD; n=23) to those who had a more favorable response of stable disease or better (SD, PR and CR abbreviated going forward as SD / CR or CR / SD; n=18), as well as stratification based on baseline CD3+ T cell infiltration, comparing tumors with low CD3+ T cell infiltration (CD3 IHC score 0, 1, and 2; CD3-low) to those with medium to high infiltration (CD3 IHC score 3 and 4; CD3-med / high) (FIG 1B). This dual stratification aimed to uncover shared pathways that could reveal universal features of the TME associated with GBM / HGG response to CAR T cell therapy. The dataset comprised 52,751 single-cell transcriptomes representingAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017tumor, stromal, and immune compartments across patients. We isolated 28,156 immune and stromal cells and applied a supervised lineage approach to classify 24 distinct immune cell populations (FIG 1C). The proportions of cells annotated for each cluster in FIG.1C across tumor samples from the 41 donors are shown in FIG.1D and clustering analysis of the 28,156 immune and stromal cells shown in FIG. 1E. Expression of marker features among the immune and stromal cells and expression status of discriminating features for each cluster is shown in FIG 1F. The differences in immune and stromal cell type proportions between complete response / stable disease (CR / SD) and progressive disease (PD) and GBM tumors with high (3- 4) and low (0-2) IHC CD3 scores are shown in FIG.1G. To identify pretreatment cellular communication networks underlying clinical response to CAR T therapy, we evaluated receptor-ligand interaction probabilities among known cell-cell communication networks by calculating the sum of communication probabilities among all pairs of cell types in the TME subsets as well as the whole tumor. In favorably responding patients, those who achieved SD / CR or had increased intra-tumoral CD3 infiltrates, the pretreatment TME signaling patterns were significantly different from non-responders (FIG 1H). Specifically, MHC-presentation pathways, including both MHCI and MHCII, were up-regulated in responding patients (SD / CR and CD3-med / high; p < 0.01) when considering the whole tumor (FIGS 1C-1D) as well as the TME subset (FIGS 1E-1H). Consistent with this observation, total lymphocyte proportions (Lymph 1 and Lymph 2) were significantly increased in SD / CR compared to PD (FIGS 1D-1G). These results align with improved patient outcomes following CAR T cell therapy being associated with higher pretreatment intratumoral T cell levels, as assessed by immunohistochemistry, and increased IFN-signaling, as previously reported. By contrast, in non-responding patients (PD, CD3-low), extracellular matrix signaling pathways were significantly up-regulated (FIG 1H). This included increased intercellular signaling for extracellular matrix components such as collagen, Cyclophilin A (CyPA), and Visfatin (FIG 1H). Notably, the extracellular matrix protein SPP1 (Osteopontin) emerged as the most dominant intercellular communication pathway in non-responding patients (FIG 1H). Heightened intercellular communication was observed within SPP1-enriched myeloid cells and between SPP1+ myeloid and fibroblast clusters (FIGS 1F & 1I) (. Further analysis revealed that SPP1+ myeloid cells, specifically clusters M1, M2, M3, M5 and M6, as well as fibroblast cluster F3, show high expression of SPP1 and engage through three dominant cell-cell interactionAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017pathways: SPP1-CD44, MIF-CD44+CD74, and TREM2-APOE (FIGS 1F &1I-1J). These pathways are known to be associated with suppressive signaling within the TME. While high expression levels of SPP1 have been linked to poor prognosis in multiple solid tumors the role of SPP1 in mediating resistance to CAR T cell therapies is noticeably understudied. Example 2: Priming of YUMM JAK1 / KO tumors with OPN targeted monoclonal antibody before delivering mIL13 CAR T cells significantly enhances therapeutic efficacy Given the convergence of SPP1 mediated signaling associated with an immuno-suppressive TME, we hypothesized targeting SPP1 alongside CAR T cell therapy may overcome resistance. To test this, experiments were conducted in three preclinical models of solid tumors with known suppressive TMEs and IFN deficiencies. To evaluate the functional impact of SPP1 in promoting solid tumor resistance to CART cell therapy, we employed a combined strategy using an anti-SPP1 antibody alongside CAR T cell therapy targeting YUMM JAK1 / KO and MC38 JAK1 / KO tumors (FIG.4A). The YUMM JAK1 / KO melanoma model was used as well as an additional IFN signaling deficient tumor model, MC38 JAK1 / KO. Similar to YUMM tumor sublines, MC38 JAK1 / KO is engineered to express IL13Rα2. In both models we employed a dual approach using an anti-SPP1 blocking antibody in combination with mIL13Rα2 CAR T cell therapy. We administered three doses of anti-SPP1 prior to CAR T cell therapy in one arm, while in another arm, anti-SPP1 was delivered concurrently with CAR T cells and continued for three doses. Analysis of the YUMM JAK1 / KO tumor volumes revealed a significant reduction in size of tumors in sequentially treated group compared to a modest reduction in concomitant treated group (FIG 4B, left graph). Similar results were observed in MC38 JAK1 / KO models, where pre-treatment with anti-SPP1 followed by mIL13CAR T cell therapy demonstrated significant tumor responses (FIG 4B, right graph). We next conducted RNA bulk sequencing on YUMM JAK1 / KO tumors primed with the anti- SPP1 antibody before CAR T cell therapy and compared them to groups treated with SPP-1 antibody alone, CAR T cell therapy alone, and control groups (FIG 4C). The results demonstrated that tumors primed with anti-SPP1 showed increased levels of dendritic cells, activated T cells, and inflammatory macrophages. These findings underscore the significance of SPP-1 blockade in reprogramming the TME, thereby enhancing its receptiveness to overcome resistance to mIL13 CAR T cells.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017To examine the impact of SPP1 modulation on CAR T therapy in gliomas, we extended these studies to a mouse glioma model; tissues from three distinct syngeneic glioma tumors were stained for SPP1. All tumors exhibited elevated SPP1 expression, with Kluc showing particularly higher levels (FIG 4D). Kluc, a firefly luciferase-engineered subline of KR158 derived from spontaneous gliomas in Nf1, Trp53 mutant mice, mirrors the invasive features of GBM and is known for notable resistance to immunotherapies. Furthermore, tissue from Kluc tumors recapitulate SPP1 driven features associated with poor CAR T outcomes in human GBM / HGG as our experience indicates that Kluc tumors are more resistant to mIL13Ra2 targeted CAR T cell therapies, aligning with the inverse correlation of SPP1 expression and CAR T cell therapy response. Almost all SPP1-expressing cells also showed CD68 expression, suggesting that SPP-1 is predominantly expressed on macrophages. We then combined anti-SPP1 therapy with CAR T cell therapy against the Kluc orthotopic tumors (FIG 4E). Flux values (FIG 4F & 4I) and survival analysis (FIG 4G-4I) revealed that the combination group, primed with anti-SPP1 and continuing to receive anti-SPP1 after CAR T cell therapy, exhibited a significantly better response compared to tumors treated with anti-SPP1 alone or CAR T cells alone. These preclinical findings support the notion that SPP1 fuels the suppressive niche and promotes tumor resistance to CAR T cell therapy. Sequential blockade of SPP-1 and CAR T cell therapy overcomes resistance in multiple tumor models. Example 3: Multifunctional SPP1-expressing myeloid cells are associated with therapeutic resistance to CAR T cell therapy in GBM / HGGs To further elucidate the clinical significance of SPP1 expression in response to CAR T cell therapy, we first analyzed its relationship with survival across GBM / HGG tumors, revealing a significant inverse correlation (R = 0.13, p = 0.03; FIG.2A & 2K). Given that SPP1 was primarily derived from myeloid cells, we next examined whether the abundance of SPP1 High myeloid cells correlated with survival and found a similarly significant inverse relationship, indicating their role in driving CAR T cell resistance (FIG.2L). Further analysis confirmed a negative correlation between SPP1 expression in myeloid cells and survival in GBM / HGG patients (FIG.2C). SPP1 High tumors exhibited a shift toward myeloid dominance with a reduced lymphoid-to-myeloid ratio, further highlighting the role of SPP1 expressing myeloid cells in modulating therapeutic response (Χ2= 9.23 p-value = 0.002, FIG 2C).Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017We next sought to determine the association of SPP1 expression with a suppressive niche linked to poor outcomes in GBM / HGGs, by evaluating differential expression of SPP1 across myeloid subclusters (FIG 2B). Of the five myeloid subclusters identified to have high to intermediate SPP1 expression (SPP1hi / int; M1, M2, M3, M5 and M6), significantly higher SPP1 expression was observed in patients displaying poor outcomes to CAR T cell therapy, both PD and CD3-low tumors (FIG.2B). Of note, the M6 subcluster was never present in CD3-high tumors and its abundance was significantly increased in PD patients (FIG 1H). M6 is marked by elevated expression of immunosuppressive genes such as C1Q subtypes, CD163, CCL4, TYROBP, TREM2, APOE, and is one of myeloid subclusters with the highest expression of SPP1 (FIGS 2H-2I). While M1, M2, M3, and M5 make up a significant portion of the suppressive myeloid cell population within the tumors and higher SPP1 expression was associated with poor outcomes to CAR therapy, total subcluster abundance was not significantly differentially distributed in outcome comparisons (FIGS 2H-2I). Additionally, the fibroblast subcluster F3 exhibits high SPP1 and APOE expression and is enriched in PD and CD3 low non-responding groups compared to their corresponding counterparts (FIGS 2H-2I). In contrast, M4, M8, and M9 are SPP1-negative myeloid cells lacking suppressive features, such as TREM2, IL1B, and CCL4 (FIGS 2H-2I). Of note, M9 is a CD4+ expressing subcluster with upregulation of GZMB potentially representing activated myeloid cells and is found in greater abundance in SD / CR group (FIGS 2H-2I). Immunofluorescent staining of PD tumor samples compared to SD / CR tumor samples confirmed differences in SPP1 expression non-responding patients, consistent with transcriptomic findings (FIGS 2H-2j). Collectively, these findings highlight a potential unrealized role for SPP1 in suppressing the response to CAR T cell therapy. Bridging transcriptomic data to the functional states of myeloid cells, we investigated the multifunctionality of the myeloid niche associated with CAR T cell resistance by comparing myeloid cells from SPP1 High patient tumors exhibiting poorer responses and SPP1 Low tumors exhibiting better responses (FIG.2C). To this end, we calculated gene set enrichment across curated pathways on a single cell level. SPP1 High myeloid cells demonstrated significant enrichment in lipid metabolism and oxidative phosphorylation pathways, characterized by upregulation of lipid-related genes such as APOC1, APOE, and FABP5 (FIGS. 2E & 2G). This metabolic profile suggests an increased reliance on non-glycolytic ATP production, indicative of their suppressive phenotype.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017In addition to their altered metabolic profile, SPP1 High myeloid cells displayed upregulation of suppressive interleukin (IL) signaling pathways (FIG.2F), in stark contrast to the inflammatory IL pathways enriched in SPP1 Low myeloid cells. Elevated ligand-receptor interactions, particularly involving FGFR and its ligands, were also observed in SPP1 High myeloid cells (FIG.2F). Furthermore, pathways associated with increased ECM activity and hypoxia, along with decreased phagocytosis and a marked downregulation of antigen processing and presentation pathways were associated with SPP1 High myeloid cells (FIGS.2E & 2F). Together, these data demonstrate a coordinated phenotypic shift associated with increased SPP1 expression consistent with driving a suppressive TME. Example 4: Conserved TME features associated CAR T cell resistance across solid tumors We next conducted an integrative analysis comparing scRNA-seq data from GBM / HGG patients paired with mouse JAK1 / KO and WT YUMM tumors (FIG.3A-3B & 30A-30B). Strikingly, this analysis revealed a high concordance between GBM / HGGs and IFN-deficient, but not WT, mouse melanoma tumors, highlighting the universality and conservation of key TME features driving resistance to CAR T cell therapy in solid tumors (FIG.3C & 30C-30D). GBM / HGGs and JAK1 / KO tumors showed strong concordance in the high expression of canonical suppressive macrophage and fibroblast markers. These genes include APOE, C1QA, C1QB, C1QC, COL1A1, and SPP1, all expressed in multiple integrated macrophage subclusters, as well as S100A8 and S100A9, which were expressed in neutrophil subclusters. In contrast, these genes were not as correlated in the comparison of GBM / HGGs and YUMM WT tumors that were more responsive to CAR T cell therapy (FIG.30E). Collectively, the expression of these conserved signatures across immune components predominantly shapes the suppressive TME, thereby reinforcing its unresponsiveness to CAR T cell therapy. These findings suggest that despite diverse tumor-intrinsic resistance mechanisms to CAR T cell therapy—such as those observed in patient GBM / HGG and IFN signaling- deficient mouse tumors—resistance ultimately is conferred by shared suppressive features of the TME, primarily driven by SPP1+ myeloid populations and extracellular matrix remodeling.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Example 5: IFN-deficient solid tumors suppress CAR T cell responses through an altered suppressive TME that is linked to increased SPP1+ macrophages Based on the findings that SPP1 High myeloid cells in human GBM / HGGs were associated with depleted IFN signaling and antigen presentation, we performed parallel orthogonal studies in syngeneic mouse models to explore the dependency of CAR T cell responses on intact tumor IFN signaling and antigen presentation. While defective IFN signaling has been shown to impair CAR T cell-mediated killing via direct tumor cell-intrinsic mechanisms involving T cell-tumor cell interactions, the broader impact on shaping the TME and influencing CAR T cell responses remains largely unexplored. To this end, we leveraged JAK1-knockout (JAK1 / KO) melanoma tumors (YUMM), which are defective in type I and II IFN signaling and exhibit low baseline MHC expression and are known to be resistant to immune checkpoint blockade and adoptive transfer of TCR-targeted tumor-specific T cells due to defective antigen presentation. IL13Rα2-engineered YUMM JAK1 / KO and WT tumor cells were injected subcutaneously into immunocompetent mice and treated with murine IL13Rα2-targeted CAR (mIL13Rα2 CAR) T cells administered intravenously (IV) (FIG.29A). YUMM JAK1 / KO tumors demonstrated significant resistance to IV delivered mIL13Rα2 CAR T cell therapy as compared to WT YUMM counterparts (FIG.29B). Further, JAK1 / KO tumors displayed a significantly reduced number of circulating CD3+ and CAR T cells in the blood (FIGS.29C-29D). Similar results were also observed when CAR T cells were administered intratumorally (IT) (FIGS.3D-3E & 29E-29F), suggesting that the limited therapeutic activity in YUMM JAK1 / KO tumors could not solely be explained by defects in trafficking. We next evaluated the potential role of the TME in mediating resistance to mIL13Rα2 CAR T cells in JAK1 / KO models. We performed paired single cell analyses of YUMM JAK1 / KO and WT tumors following mIL13Rα2 CAR T cell IT treatment (FIGS.3F & 29G). We found cell type differences between YUMM WT and YUMM JAK1 / KO were largely consistent in both untreated and mIL13Rα2 CAR T treated mice, suggesting the endogenous suppressive TME is maintained through therapy (FIGS.3G & 29H). We found a significant enrichment of macrophages and stromal cells in the YUMM JAK1 / KO mice and an enrichment of B and T cells in the WT mice (FIGS.3G-3I & 29H-29I). Furthermore, from our scRNA-seq analysis we wereAttorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017able to identify the proportion of mIL13Rα2 CAR T cells in the tumors and found a significantly lower proportion within YUMM JAK1 / KO compared to WT (FIGS.3D-3E & 29J). Comparative cell-cell signaling analyses highlighted significant differences for intercellular communication pathways in YUMM JAK1 / KO tumors, particularly those regulating ECM scaffold, remodeling and regeneration, such as collagen, fibronectin, and laminin (FIG.29K). Consistent with findings from GBM / HGGs, SPP1 emerged as one of the top upregulated pathways in YUMM JAK1 / KO tumors, while MHCII was notably upregulated in WT tumors (FIG. 29K). Cell-cell communication analysis further demonstrated increased interaction probabilities between fibroblasts and myeloid cells in YUMM JAK1 / KO tumors relative to YUMM WT, with SPP1 representing one of the most prominent pathways driving these interactions (FIGS.29K- 29L). Notably, both SPP1 and its cognate receptor CD44 were significantly upregulated across all immune-driven populations, including fibroblasts, neutrophils, and myeloid cells, in JAK1 / KO tumors compared to YUMM WT (FIGS.3H & 29M). Together, these data demonstrate how the IFN signaling-deficient JAK1 / KO tumor microenvironment fosters an immunosuppressive niche, markedly involving SPP1 and contributing to resistance against mIL13Rα2 CAR T therapy. EXAMPLE 6: SPP1 antibody restores SPP1-mediated suppression of human CAR T cell proliferation and activation Experiments were designed to test the effect of SPP1 on CAR T cell proliferation and activation, as well as the ability of an SPP1 antibody to restore any loss in function. Human IL13Rα2-CAR T cell stained by CFSE was activated using human IL13Rα2-Fc or 2.5 µg / mL anti-CD3 in the presence and absence of 10 µg / mL recombinant human SPP1 to measure the effect on the T cell proliferation and activation as measured by CD69+41BB+ (FIG. 32). Generally, the results demonstrate that SPP1 inhibits IL13Ra2-Fc-mediated CAR T cell activation and proliferation. As shown in FIG.32, the IL13Rα2-CAR T cells were successfully activated when incubated with more than 125 µg of human recombinant IL13Rα2-Fc (through CAR signaling). The addition of human recombinant SPP1 suppresses CAR T cell proliferation and activation. However, this suppressive effect is not observed when CAR T cells are incubated with 500 µg of IL13Rα2-Fc.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017Further, human IL13Rα2-CAR T cell stained by CFSE was activated by 2.5 µg / mL anti-CD3 and incubated with indicated concentration of human recombinant SPP1 (rhSPP1) in FIGS.31A- 31B. Cell proliferation and activation as measured by CD69+CD25+ was detected. Human recombinant SPP1 is able to inhibits the proliferation of IL13Rα2-CAR T cell (activated through TCR signaling) in a dose-dependent manner (FIG.31A). Similarly, the activation level of IL13Rα2-CAR T cell, as indicated by the proportion of CD69+CD25+ population, is notably inhibited by human recombinant SPP1 (FIG.31A). To test if an SPP1 antibody could alleviate the observed SPP1 inhibition on CAR T cells proliferation and activation, an anti-SPP1 mAb was added at the indicated concentration to human IL13Rα2-CAR T cell stained by CFSE and activated by 2.5 µg / mL anti-CD3 in the presence and absence of 10 µg / mL rhSPP1 (FIG.31B). Again, Cell proliferation and activation as measured by CD69+CD25+ was detected. The addition of anti-SPP1 antibody partially reversed SPP1-mediated suppression on CAR T cell proliferation and activation, while the antibody alone has no notable effect on CAR T cell proliferation and activation (FIG.31B). Therefore, human recombinant SPP1 is able to suppress human CAR T cell proliferation and activation, which is partially reversed by SPP1 blockade. OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017What is claimed is:

1. An antibody targeted to SPP1 comprising: a variable light chain comprising of any one of: i. CDR1 comprising or consisting of SEQ ID NO:P2; CDR2 comprising or consisting of SEQ ID NO:P3; and CDR3 comprising or consisting of SEQ ID NO:P4; ii. CDR1 comprising or consisting of SEQ ID NO:P10; CDR2 comprising or consisting of SEQ ID NO: P11; and CDR3 comprising or consisting of SEQ ID NO: P12); iii. CDR1 comprising or consisting of SEQ ID NO:P18; CDR2 comprising or consisting of SEQ ID NO: P19; and CDR3 comprising or consisting of SEQ ID NO: P20); iv. CDR1 comprising or consisting of SEQ ID NO:P26; CDR2 comprising or consisting of SEQ ID NO: P27; and CDR3 comprising or consisting of SEQ ID NO:P28); v. CDR1 comprising or consisting of SEQ ID NO:P34; CDR2 comprising or consisting of SEQ ID NO: P35; and CDR3 comprising or consisting of SEQ ID NO: P36); vi. CDR1 comprising or consisting of SEQ ID NO:P42; CDR2 comprising or consisting of SEQ ID NO: P43; and CDR3 comprising or consisting of SEQ ID NO:P44); vii. CDR1 comprising or consisting of SEQ ID NO:P50; CDR2 comprising or consisting of SEQ ID NO: P51; and CDR3 comprising or consisting of SEQ ID NO:P52); viii. CDR1 comprising or consisting of SEQ ID NO:P58; CDR2 comprising or consisting of SEQ ID NO: P59; and CDR3 comprising or consisting of SEQ ID NO:P60); ix. CDR1 comprising or consisting of SEQ ID NO:P66; CDR2 comprising or consisting of SEQ ID NO: P67; and CDR3 comprising or consisting of SEQ ID NO:P68); x. CDR1 comprising or consisting of SEQ ID NO:P74; CDR2 comprising or consisting of SEQ ID NO:P75; and CDR3 comprising or consisting of SEQ ID NO:P76);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xi. CDR1 comprising or consisting of SEQ ID NO:P82; CDR2 comprising or consisting of SEQ ID NO: P83; and CDR3 comprising or consisting of SEQ ID NO:P84); xii. CDR1 comprising or consisting of SEQ ID NO:P90; CDR2 comprising or consisting of SEQ ID NO: P91; and CDR3 comprising or consisting of SEQ ID NO:P92); xiii. CDR1 comprising or consisting of SEQ ID NO:P98; CDR2 comprising or consisting of SEQ ID NO: P99; and CDR3 comprising or consisting of SEQ ID NO:P100); xiv. CDR1 comprising or consisting of SEQ ID NO:P106; CDR2 comprising or consisting of SEQ ID NO: P107; and CDR3 comprising or consisting of SEQ ID NO:P108); xv. CDR1 comprising or consisting of SEQ ID NO:P114; CDR2 comprising or consisting of SEQ ID NO: P115; and CDR3 comprising or consisting of SEQ ID NO:P116); xvi. CDR1 comprising or consisting of SEQ ID NO:P122; CDR2 comprising or consisting of SEQ ID NO: P123; and CDR3 comprising or consisting of SEQ ID NO: P124); xvii. CDR1 comprising or consisting of SEQ ID NO:P130; CDR2 comprising or consisting of SEQ ID NO: P131; and CDR3 comprising or consisting of SEQ ID NO:P132); xviii. CDR1 comprising or consisting of SEQ ID NO:P138; CDR2 comprising or consisting of SEQ ID NO: P139; and CDR3 comprising or consisting of SEQ ID NO:P140); xix. CDR1 comprising or consisting of SEQ ID NO:P146; CDR2 comprising or consisting of SEQ ID NO: P147; and CDR3 comprising or consisting of SEQ ID NO:P148); xx. CDR1 comprising or consisting of SEQ ID NO:P154; CDR2 comprising or consisting of SEQ ID NO: P155; and CDR3 comprising or consisting of SEQ ID NO:P156); xxi. CDR1 comprising or consisting of SEQ ID NO:P162; CDR2 comprising or consisting of SEQ ID NO: P163; and CDR3 comprising or consisting of SEQ ID NO:P164);Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xxii. CDR1 comprising or consisting of SEQ ID NO:P170; CDR2 comprising or consisting of SEQ ID NO: P171; and CDR3 comprising or consisting of SEQ ID NO:P172); and xxiii. CDR1 comprising or consisting of SEQ ID NO:P178; CDR2 comprising or consisting of SEQ ID NO: P179; and CDR3 comprising or consisting of SEQ ID NO:P180; and a variable heavy chain comprising of any one of: i. CDR1 comprising or consisting of SEQ ID NO:P6; CDR2 comprising or consisting of SEQ ID NO:P7; and CDR3 comprising or consisting of SEQ ID NO:P8; ii. CDR1 comprising or consisting of SEQ ID NO: P14; CDR2 comprising or consisting of SEQ ID NO: P15; and CDR3 comprising or consisting of SEQ ID NO:P16; iii. CDR1 comprising or consisting of SEQ ID NO:P22; CDR2 comprising or consisting of SEQ ID NO: P23; and CDR3 comprising or consisting of SEQ ID NO:P24; iv. CDR1 comprising or consisting of SEQ ID NO:P30; CDR2 comprising or consisting of SEQ ID NO: P31; and CDR3 comprising or consisting of SEQ ID NO:P32; v. CDR1 comprising or consisting of SEQ ID NO:P38; CDR2 comprising or consisting of SEQ ID NO: P39; and CDR3 comprising or consisting of SEQ ID NO:P40; vi. CDR1 comprising or consisting of SEQ ID NO:P46; CDR2 comprising or consisting of SEQ ID NO: P47; and CDR3 comprising or consisting of SEQ ID NO:P48; vii. CDR1 comprising or consisting of SEQ ID NO:P54; CDR2 comprising or consisting of SEQ ID NO: P55, and CDR3 comprising or consisting of SEQ ID NO:P56; viii. CDR1 comprising or consisting of SEQ ID NO:P62; CDR2 comprising or consisting of SEQ ID NO: P63; and CDR3 comprising or consisting of SEQ ID NO:P64; ix. CDR1 comprising or consisting of SEQ ID NO:P70; CDR2 comprising or consisting of SEQ ID NO: P71; and CDR3 comprising or consisting of SEQ ID NO:P72;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017x. CDR1 comprising or consisting of SEQ ID NO:P78; CDR2 comprising or consisting of SEQ ID NO: P79; and CDR3 comprising or consisting of SEQ ID NO:P80; xi. CDR1 comprising or consisting of SEQ ID NO:P86; CDR2 comprising or consisting of SEQ ID NO: P87; and CDR3 comprising or consisting of SEQ ID NO:P88; xii. CDR1 comprising or consisting of SEQ ID NO:P94; CDR2 comprising or consisting of SEQ ID NO: P95; and CDR3 comprising or consisting of SEQ ID NO:P96; xiii. CDR1 comprising or consisting of SEQ ID NO:P102; CDR2 comprising or consisting of SEQ ID NO: P103; and CDR3 comprising or consisting of SEQ ID NO:P104; xiv. CDR1 comprising or consisting of SEQ ID NO:P110; CDR2 comprising or consisting of SEQ ID NO: P111; and CDR3 comprising or consisting of SEQ ID NO:P112; xv. CDR1 comprising or consisting of SEQ ID NO:P118; CDR2 comprising or consisting of SEQ ID NO: P119; and CDR3 comprising or consisting of SEQ ID NO: P120; xvi. CDR1 comprising or consisting of SEQ ID NO:P126; CDR2 comprising or consisting of SEQ ID NO: P127; and CDR3 comprising or consisting of SEQ ID NO:P128; xvii. CDR1 comprising or consisting of SEQ ID NO:P134; CDR2 comprising or consisting of SEQ ID NO: P135; and CDR3 comprising or consisting of SEQ ID NO:P136; xviii. CDR1 comprising or consisting of SEQ ID NO:P142; CDR2 comprising or consisting of SEQ ID NO: P143; and CDR3 comprising or consisting of SEQ ID NO:P144; xix. CDR1 comprising or consisting of SEQ ID NO:P150; CDR2 comprising or consisting of SEQ ID NO: P151; and CDR3 comprising or consisting of SEQ ID NO:P152; xx. CDR1 comprising or consisting of SEQ ID NO:P158; CDR2 comprising or consisting of SEQ ID NO: P159; and CDR3 comprising or consisting of SEQ ID NO:P160;Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-017xxi. CDR1 comprising or consisting of SEQ ID NO:P166; CDR2 comprising or consisting of SEQ ID NO: P167; and CDR3 comprising or consisting of SEQ ID NO:P168; xxii. CDR1 comprising or consisting of SEQ ID NO:P174; CDR2 comprising or consisting of SEQ ID NO: P175; and CDR3 comprising or consisting of SEQ ID NO:P176; and xxiii. CDR1 comprising or consisting of SEQ ID NO:P182; CDR2 comprising or consisting of SEQ ID NO: P183; and CDR3 comprising or consisting of SEQ ID NO:P184.

2. The antibody of claim 1, wherein the variable light chain comprises the amino acid sequence of any one of SEQ ID NOs: P1, P9, P17, P25, P33, P41, P49, P57, P65, P73, P81, P89, P97, P105, P113, P121, P129, P137, P145, P153, P161, P169, P177, and variants thereof with 1-5 single amino acid modifications (e.g., 1 or 2 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs; and the variable heavy chain comprises the amino acid sequence of any one of SEQ ID NOs: P5, P13, P21, P29, P37, P45, P53, P61 , P69, P77, P85, P93, P101, P109, P117, P125, P133, P141, P149, P157, P165, P173, P181 and variants thereof with 1-5 single amino acid modifications (e.g., 1 or 2 single amino acid substitutions), wherein the modifications (e.g., substitutions) are not in the CDRs.

3. The antibody of claim 1, wherein the antibody comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 213, P1, P9, P17, P25, P33, P41, P49, P57, P65, P73, P81, P89, P97, P105, P113, P121, P129, P137, P145, P153, P161, P169, P177, and variants thereof with 1-10 single amino acid modifications (e.g., 1, 2, 3, 4, 5, or 6 single amino acid substitutions), wherein the amino acid modifications (e.g., amino acid substitutions) are not in the CDRs; and the antibody comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 214, P5, P13, P21, P29, P37, P45, P53, P61 , P69, P77, P85, P93, P101, P109, P117, P125, P133, P141, P149, P157, P165, P173, P181, and variants thereof with 1-10 single amino acid modifications (e.g., 1, 2, 3, 4, 5, or 6 single amino acid substitutions), wherein the amino acid modifications (e.g., amino acid substitutions) are not in the CDRs.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-0174. A method for treating a human patient suffering from a cancerous solid tumor, the method comprising: (a) administering to the patient an antibody targeted to osteopontin (SPP-1); and (b) administering to the patient a population of immune cells expressing a chimeric antigen receptor (CAR) targeted to a solid tumor antigen.

5. The method of claim 4, wherein the solid tumor antigen is selected from the group consisting of: an IL-13 receptor alpha, MMP2, CD70, B7H3, TAG72, EGFR, HER2, PSCA, and PSMA.

6. The method of claim 4, wherein the CAR comprises: (i) an antigen binding domain that binds the solid tumor antigen; (ii) a spacer domain; (iii) a transmembrane domain; (iv) a costimulatory domain; and (v) a CD3ζ signaling domain.

7. The method of claim 4, wherein the antigen binding domain is human IL-13 or a variant thereof, a chlorotoxin or a variant thereof, an scFv targeted to HER2, an scFv targeted to B7H3, an scFv targeted to an EGFR, an scFv targeted to CD70, an scFv targeted to TAG72, an scFv targeted to PSCA, or an scFv targeted to PSMA.

8. The method of any one of claims 4-7, wherein the CAR comprises an amino acid sequence selected from SEQ ID NOs:101-212 and variants thereof having 1-10 (e.g., 1, 2, 3, 4, 5, 6, or 7) single amino acid modifications (e.g., amino acid substitutions), wherein the modification (e.g., substitutions) are not in the antigen binding domain.

9. The method of any of claims 4-8, wherein the SSP1 antibody is administered prior to administration of the population of CAR immune cells.

10. The method of any of claims 9, wherein the SSP1 antibody is first administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days prior to administration of the population of CAR immune cells.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-01711. The method of any of claims 4-6 wherein the SSP1 antibody is administered at least 2 times.

12. The method of any of claims 4-11 wherein the SSP1 antibody is administered two or more times and one administration is concurrently with the population of CAR immune cells.

13. The method of any of claims 4-12 wherein the SSP1 antibody is administered two or more times and at least one administration is subsequent to administration of the population of CAR immune cells.

14. The method of any of claims 4-13, wherein: the spacer comprises a sequence selected from the group consisting of: SEQ ID NOs: 24-34; the transmembrane domain comprises a sequence selected from the group consisting of SEQ ID NOs: 15-23; the costimulatory domain comprises a sequence selected from the group consisting of SEQ ID NOs: 36-40, and the CD3ζ signaling domain comprises SEQ ID NO:

35.

15. The method of claim 14, wherein the spacer region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-34.

16. The method of claim 14, wherein the transmembrane domain selected from the group consisting of: a CD4 transmembrane domain, a CD8 transmembrane domain, a CD28 transmembrane domain, and a CD3ζ transmembrane domain.

17. The method of claim 14, wherein the costimulatory domain selected from the group consisting of a CD28 costimulatory domain, a 41-BB costimulatory domain, an OX40 costimulatory domain, and a 2B4 costimulatory domain.Attorney Docket No.: 40056-0107WO1 / COH Ref: TEC 24-01718. The method claim 14, wherein the chimeric antigen receptor comprises the amino acid sequence of any one of SEQ ID NOs: 101-212 with 0, 1, 2, 3, 4 or 5 single amino acid substitutions; optionally wherein the amino acid substitutions are not in the antigen binding domain.

19. The method of claim 14, further comprising a linker consisting of 1 – 5 amino acids between one or more of: the antigen binding domain (e.g., the scFv) and the spacer domain, the spacer domain and the transmembrane domain, the transmembrane domain and the co- stimulatory domain, and the costimulatory domain and the CD3ζ signaling domain.

20. The method of claim 19, wherein interdomain linker consists of 1-5 glycines.

21. The method of claim 14, wherein an interdomain linker consisting of the sequence GGG is located between the costimulatory domain and the CD3ζ signaling domain.

22. A method for treating a human patient suffering from a cancerous solid tumor comprising cells expressing a solid tumor antigen, the method comprising: (a) administering to the patient the antibody of claim 1; and (b) administering to the patient a population of immune cells expressing a chimeric antigen receptor (CAR) targeted to the solid tumor antigen.

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