Method of treating prame-positive cancer

Abstract

The present disclosure provides a method of treating non-small or small cell lung cancer, or ovarian carcinoma, in a subject, comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, for example wherein the second active agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi-modal therapy (e.g. a chemotherapeutic agent and a targeted therapy), in a dosing regimen, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 μg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 μg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days, wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule.

Description

Atty. Docket No.0282-0009WO2 METHOD OF TREATING PRAME-POSITIVE CANCER FIELD OF THE INVENTION

[0001] The present disclosure provides a method of treating non-small or small cell lung cancer, or ovarian carcinoma, in a subject, comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, for example wherein the second active agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi- modal therapy (e.g. a chemotherapeutic agent and a targeted therapy), in a dosing regimen, wherein the dosing regimen comprises administering: (a) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (b) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (c) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days, wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule. BACKGROUND

[0002] Preferentially expressed antigen in melanoma (PRAME) is a nuclear receptor and transcriptional regulator and a member of cancer testis antigen (CTA) family of proteins. In normal tissue, PRAME is expressed almost exclusively in the testis. Physiologically, it acts as a repressor of retinoic acid receptor pathway and thereby regulates cell differentiation, growth, and apoptosis. Because PRAME is recognized by tumor-reactive cytotoxic T cells, there may be rationale for anti-PRAME immunotherapy and need to assess PRAME immunopositivity in search of treatment targets. PRAME is frequently highly expressed in a range of solid and hematologic malignancies including melanoma, ovarian carcinoma, uterine carcinoma, small-cell and non-small cell lung cancer, triple-negative breast cancer, and several rare tumor types.

[0003] Current recommended treatments for cancer such as unresectable or metastatic disease provide critical treatment options for patients. Such treatments, for example, for lungAtty. Docket No.0282-0009WO2 cancer, include anti-PD-1-based regimens for subjects which are considered as standard of care (SoC) for initial treatment in many settings. Such SoC treatments also include, for example, for ovarian cancer, surgery and / or chemotherapy in first line or induction settings. Despite these options, at least half of these subjects will progress within 1 year. For patients with advanced cancers an unmet need remains for additional treatment options. Cancer treatment is complex and can vary significantly depending on stage of disease, prior treatments, and tumor type, and the significant heterogeneity across individual patients is often underestimated. Even within a certain type of cancer, or tumor type, patients can have different underlying complexity, making design of trials and interpretation of results complicated. Clinical trials designed to evaluate the safety and efficacy of IMC-F106C, the first T-cell receptor (TCR) bispecific protein targeting PRAME and CD3, represent novel approaches for treating cancer patients.

[0004] SUMMARY OF THE INVENTION

[0005] In some aspects, the present disclosure provides a method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel), in a dosing regimen. In some aspects the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR- anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR- anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administeredAtty. Docket No.0282-0009WO2 once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose; and wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule.

[0006] In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the chemotherapeutic agent is docetaxel. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is osimertinib. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

[0007] In some aspects, the present disclosure provides a method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel), in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibodyAtty. Docket No.0282-0009WO2 fusion molecule than the second dose; and wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule.

[0008] In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD). In some aspects, the chemotherapeutic agent is carboplatin / paclitaxel. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is bevacizumab. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0009] In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose comprises 2 to 4 ug of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 5 to 14 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 15 to 55 µg of the TCR-anti-CD3 antibody fusion molecule. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose comprises 3 ug of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 10 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 40 µg of the TCR-anti-CD3 antibody fusion molecule. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose comprises 15 to 40 µg of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 30 to 80 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 140 to 200 µg of the TCR-anti-CD3 antibody fusion molecule. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose comprises 20 µg of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 40 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 160 µg of the TCR-anti-CD3 antibody fusion molecule.

[0010] In some aspects, the alpha chain amino acid sequence of the TCR-anti-CD3 antibody has 100% identity to the amino acid sequence of SEQ ID NO: 14. In some aspects, the beta chain amino acid sequence has 100% identity to the amino acid sequence of SEQ ID NO: 16.Atty. Docket No.0282-0009WO2

[0011] In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose is administered once every 7 days. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose is administered for 1 week to about 3 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose is administered for 1 week. In some aspects, the second dose is administered 6 to 8 days following the first dose. In some aspects (for example, the methods described herein that may provide a dosing regimen), the second dose is administered once every 7 days. In some aspects (for example, the methods described herein that may provide a dosing regimen), the second dose is administered for 1 week to about 3 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the second dose is administered for 1 week.

[0012] In some aspects (for example, the methods described herein that may provide a dosing regimen), the maintenance dose in the first phase is administered 6 to 8 days following the second dose. In some aspects (for example, the methods described herein that may provide a dosing regimen), the maintenance dose in the first phase is administered once in a week. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first phase is about 2 weeks to about 101 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first phase is about 8 weeks to about 14 weeks. In some aspects, the first phase is 10 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the maintenance dose in the second phase is administered once every 2 weeks. In some aspects (for example, the techniques described herein that may relate to a method), the second phase is about 30 weeks to 50 weeks. In some aspects, the second phase is 38 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the maintenance dose in the third phase is administered every 4 weeks. In some aspects (for example, the techniques described herein that may relate to a method), the third phase is about 40 weeks to about 60 weeks. In some aspects (for example, the techniques described herein that may relate to a method), the third phase is about 48 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first phase is 10 weeks, the second phase is 38 weeks, and the third phase is 48 weeks. In some aspects (for example, the methods described herein that may provide a dosing regimen), the first dose is administered for 1 week, the second dose is administered for 1 week, and the maintenanceAtty. Docket No.0282-0009WO2 dose is administered for at least 40 weeks. In some aspects, the dosing regimen is about 90 weeks to about 110 weeks.

[0013] In some aspects (for example, wherein the disclosure provides a method), no corticosteroids are administered within three weeks prior to the dosing regimen and throughout the dosing regimen. In some aspects (for example, wherein the disclosure provides a method of administering to a subject), the subject is HLA-A*02 positive. In some aspects, the subject is HLA-A*02:01 positive. In some aspects, the subject has BRAF V600 mutation. In some aspects, the subject has been diagnosed with a life expectancy greater than 3 months.

[0014] In some aspects (for example, wherein the disclosure provides a method), the second active agent is co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects, the second active agent is first administered 1 to 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects, the second active agent is administered 1 to 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered after treatment with the second active agent is complete. In some aspects, the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects (for example, the methods described herein that may provide a dosing regimen), the second active agent is administered for at least 10 weeks. In some aspects, the second active agent is administered for at least 40 weeks. In some aspects, the second active agent is administered for the duration of the dosing regimen.

[0015] In some aspects (for example, wherein the disclosure provides a second active agent), the second active agent is gemcitabine. In some aspects, the gemcitabine is administered at about 750 to about 1000 mg / m2. In some aspects, the gemcitabine is administered at a dose of about 1000 mg / m2. In some aspects, the gemcitabine is administered once a week to once a month. In some aspects, the gemcitabine is administered about (i) 4 weeks on and 1 week off, (ii) 3 weeks on and 1 week off, (iii) 2 weeks on and one week off, (iv) 1 week on and 1 week off, (v) weekly, or (vi) biweekly.

[0016] In some aspects (for example, wherein the disclosure provides a second active agent), the second active agent is nab-paclitaxel. In some aspects, the nab-paclitaxel is administered at about 75 to about 100 mg / m2. In some aspects, the nab-paclitaxel isAtty. Docket No.0282-0009WO2 administered at a dose of about 100 mg / m2. In some aspects, the nab-paclitaxel is administered once a week to once a month. In some aspects, the nab-paclitaxel is administered about (i) 4 weeks on and 1 week off, (ii) 3 weeks on and 1 week off, (iii) 2 weeks on and one week off, (iv) 1 week on and 1 week off, (v) weekly, or (vi) biweekly.

[0017] In some aspects (for example, wherein the disclosure provides a second active agent), the second active agent is decitabine, e.g., low-dose decitabine. In some aspects, the decitabine is administered at about 0.07 to about 0.6 mg / kg. In some aspects, the decitabine is administered once a week to once a month. In some aspects, the decitabine is administered about (i) once a week, (ii) once every two weeks, (iii) once every three weeks, or (iv) once every month.

[0018] In some aspects, the second active agent is pegylated liposomal doxorubicin (PLD). In some aspects, the PLD is administered at about 40 mg / m2 to 60 mg / m2 every 4 weeks to every 6 weeks.

[0019] In some aspects (for example, wherein the methods described herein comprise administering a composition), the composition is administered orally, subcutaneously, sublingually, intramuscularly, intravenously, intranasally, transdermally, or any combination thereof. In some aspects, the second composition is administered orally, subcutaneously, sublingually, intramuscularly, intravenously, intranasally, transdermally, or any combination thereof

[0020] In some aspects, the present disclosure provides a method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel), in a dosing regimen, In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, theAtty. Docket No.0282-0009WO2 dosing regimen comprises: (i) administering one first dose comprising 3 µg of the TCR-anti- CD3 antibody fusion molecule, (ii) administering one second dose comprising 10 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0021] In some aspects, the present disclosure provides a method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel), in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises: (i) administering one first dose comprising 3 µg of the TCR-anti- CD3 antibody fusion molecule, (ii) administering one second dose comprising 10 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering theAtty. Docket No.0282-0009WO2 maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0022] In some aspects, the present disclosure provides a method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel), in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises: (i) administering one first dose comprising 20 µg of the TCR- anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 160 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and then every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule , during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.Atty. Docket No.0282-0009WO2

[0023] In some aspects, the present disclosure provides a method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel, in a dosing regimen), in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity- determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises: (i) administering one first dose comprising 20 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 160 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and then every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti- CD3 antibody fusion molecule.

[0024] In some aspects, the present disclosure provides a kit comprising: (i) one first container comprising a first dose comprising 2 to 4 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 5 to 14 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 15 to 55 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose (for example, of 10-1000Atty. Docket No.0282-0009WO2 mg / m2); (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering a maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR- anti-CD3 antibody fusion molecule.

[0025] In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the chemotherapeutic agent is docetaxel. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is osimertinib. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

[0026] In some aspects, the present disclosure provides a kit comprising: (i) one first container comprising a first dose comprising 20 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 40 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 160 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose (for example, of 10-1000 mg / m2); (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering a maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, and (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly forAtty. Docket No.0282-0009WO2 two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0027] In some aspects of the kit, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity- determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

[0028] In some aspects of the kit, the kit comprises 2 to 10 maintenance containers. In some aspects of the kit, the first dose, the second dose and / or the maintenance dose further comprise(s) a pharmaceutically acceptable excipient to form a first pharmaceutical formulation, second pharmaceutical formulation, and / or maintenance pharmaceutical formulation, respectively. In some aspects of the kit, the first, second and / or maintenance pharmaceutical formulation has a pH of about 6.5 to about 7.5.

[0029] In some aspects of the kit, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the dose amount of gemcitabine is 1000 mg / m2. In some aspects, the chemotherapeutic agent is docetaxel. In some aspects, the dose amount of docetaxel is 75 mg / m2. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is osimertinib. In some aspects, the dose amount of osimertinib is 80 mg. In some aspects, the dose amount of osimertinib is 40 mg. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the dose amount of carboplatin is AUC 6. In some aspects, the dose amount of paclitaxel is 200 mg / m2. In some aspects, the dose amount of pembrolizumab is 400 mg. In some aspects, the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab. In some aspects, the dose amount of carboplatin is AUC 5. In some aspects, the dose amount of carboplatin is AUC 6. In some aspects, the dose amount of pemetrexed is 500 mg / m2. In some aspects, the dose amount of pembrolizumab is 400 mg.

[0030] In some aspects, the present disclosure provides a method of treating a PRAME- positive cancer in a subject comprising administering to the subject a composition comprisingAtty. Docket No.0282-0009WO2 (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, and (II) a second composition comprising a second active agent (for example, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab- paclitaxel), in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity- determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects, the PRAME-positive cancer is a non-small cell lung cancer or ovarian cancer.

[0031] In some aspects, the present disclosure provides a method of treating platinum- sensitive ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen. In some aspects, heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%,Atty. Docket No.0282-0009WO2 at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0032] In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is bevacizumab. In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the chemotherapeutic agent is carboplatin / paclitaxel. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0033] In some aspects, the present disclosure provides a method of treating platinum- resistant ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, whereinAtty. Docket No.0282-0009WO2 the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0034] In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is bevacizumab. In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is gemcitabine. In some aspects, the chemotherapeutic agent is carboplatin / paclitaxel. In some aspects, the second active agent is a multi-modal therapy. In some aspects, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some aspects, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0035] In some aspects, the present disclosure provides a method of treating non-small cell lung cancer in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3Atty. Docket No.0282-0009WO2 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti- CD3 antibody fusion molecule.

[0036] In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is osimertinib.

[0037] In some aspects, the present disclosure provides a method of treating melanoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen. In some aspects, the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity- determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively In some aspects, the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprisingAtty. Docket No.0282-0009WO2 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0038] In some aspects, the second active agent is a second heterodimeric TCR-anti-CD3 antibody fusion molecule. In some aspects, the second heterodimeric TCR-anti-CD3 antibody fusion molecule is tebentafusp. In some aspects, the second active agent is a targeted therapy. In some aspects, the targeted therapy is dabrafenib / trametinib. In some aspects, the second active agent is a hypomethylating agent. In some aspects, the hypomethylating agent is decitabine. In some aspects, the hypomethylating agent is a low-dose decitabine. In some aspects, the second active agent is a chemotherapeutic agent. In some aspects, the chemotherapeutic agent is PLD. In some aspects, the chemotherapeutic agent is carboplatin / paclitaxel. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The following drawings form part of the present specification and are included to further demonstrate exemplary embodiments of certain aspects of the present disclosure.

[0040] FIG.1 depicts a high-level schema of the IMC-F106C-101 clinical trial, a study evaluating the safety and efficacy of IMC-F106C as monotherapy or in combination therapy (see also Example 1).

[0041] FIG.2 depicts a schematic illustration of the step-dose regimen of the IMC-F106C compound utilized in the IMC-F106C-101 trial.

[0042] FIG.3 depicts a schematic illustration of the step-dose regimens evaluated in various cohorts in the IMC-F106C-101 trial.Atty. Docket No.0282-0009WO2

[0043] FIG.4 depicts the response (by change in tumor size relative to baseline) in patients treated with combination IMC-F106C / chemotherapeutic agent treatments. FIG.4A is a graphical representation of the change in tumor size from baseline for patients treated with an IMC-F106C / nab-paclitaxel combination therapy where each bar represents an individual patient. FIG.4B is a different (spider plot) representation of the IMC-F106C / nab-paclitaxel treated patients, where the change in tumor size relative to baseline is shown over time and where each line represents an individual patient. FIG.4C is a graphical representation of the change in tumor size from baseline for patients treated with an IMC-F106C / gemcitabine combination therapy where each bar represents an individual patient. FIG.4D is a spider plot representation of the IMC-F106C / gemcitabine treated patients, where the change in tumor size relative to baseline is shown over time and where each line represents an individual patient. (see further description in Example 2).

[0044] FIG.5 depicts IMC-F106C (also referred to as PRAME ImmTAC®) molecule- dependent T cell activation of cancer cell-lines following decitabine pre-treatment. NCI- H441 (FIG.5A), NCI-H2087 (FIG.5B), and OVCAR3 (FIG.5C) cancer cell lines were pre- treated for 5 days with 75nM decitabine in tissue culture medium, or tissue culture medium alone (untreated), then used as target cells in an IFNγ ELISPOT assay with healthy donor PBMCs and a titration of PRAME ImmTAC molecule.

[0045] FIG.6 depicts the combination treatment approach designed for the IMC-F106C- 101 trial based on analyses conducted during the initial course of the trial. The compound to be combined with IMC-F106C is indicated for the different arms of the trial (C-1, C-3, C-4, C-5, D-1, E-3, E-4, F-1, G-1, G-2, G-3) and also arranged by tumor type (indicated as separate modules for lung, ovarian / uterine, melanoma and other).

[0046] FIG.7 provides low dose regimens for an exemplary heterodimeric TCR-anti-CD3 antibody fusion molecule IMC-F106C, including the first dose, second dose, and maintenance dose phases.

[0047] FIG.8 provides high dose regimens for an exemplary heterodimeric TCR-anti-CD3 antibody fusion molecule IMC-F106C, including the first dose, second dose, and maintenance dose phases.

[0048] FIG.9 provides exemplary dosing regimens of second active agents (i.e., combination partner) when administered in combination with a heterodimeric TCR-anti-CD3 antibody fusion molecule, e.g., IMC-F106C.Atty. Docket No.0282-0009WO2 DETAILED DESCRIPTION

[0049] Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0050] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0051] The use of the term “or” in the claims is used to mean “and / or,” unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0052] As used herein, the terms “comprising” (and any variant or form of comprising, such as “comprise” and “comprises”), “having” (and any variant or form of having, such as “have” and “has”), “including” (and any variant or form of including, such as “includes” and “include”) or “containing” (and any variant or form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps.

[0053] The use of the term “for example” and its corresponding abbreviation “e.g.” means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

[0054] As used herein, “about” can mean plus or minus 10% of the provided value. Where ranges are provided, they are inclusive of the boundary values. “About” can additionally or alternately mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value; or “about” can mean rounded to the nearest significant digit.

[0055] As used herein, “between” is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y.Atty. Docket No.0282-0009WO2

[0056] The term “administration” or “administering” refers to routes of introducing a compound or composition provided herein to a subject to perform its intended function. An example of a route of administration that can be used includes, but is not limited to, intravenous fusion.

[0057] The term “subject” means any subject, particularly a mammalian subject, in need of treatment. In some embodiments, the term “subject” refers to a human subject. In some embodiments, the term “subject” refers to an adult human subject. In some embodiments, the term “subject” refers to a male human subject. In some embodiments, the term “subject” refers to a female human subject. In some embodiments, the term “subject” refers to administration to a subject in need thereof, i.e., a subject having non-small or small cell lung cancer, ovarian carcinoma and / or a subject having a PRAME-positive cancer. As used herein, a “subject in need thereof” can refer to the subject for whom it is desirable to treat, e.g., a subject being diagnosed non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer as described herein. In some embodiments, the term “subject in need thereof” can refer to a subject having one or more symptoms associated with non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer, e.g., a subject having the following symptoms: coughing that gets worse or doesn't go away, chest pain, shortness of breath, wheezing, coughing up blood, abnormal vaginal discharge or bleeding after menopause, bloating or swollen feeling in the stomach, feeling full very soon after starting to eat, new urinary frequency, new constipation or other changes in bowel movements, discomfort or pain in the pelvic area, abdomen or lower back, fatigue, unexplained weight loss etc. In some embodiments, the term “subject in need thereof” can refer to a subject at high risk for suffering from non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer suitable to treatment with the heterodimeric TCR-anti-CD3 antibody fusion molecule and / or second active agent as described herein, independently of whether the subject has physical manifestations of such condition. In some embodiments, the subject is an adult, i.e., at least 18 years old. In some embodiments, the subject is 12-18 years old. In some embodiments, the subject is less than 12 years old. In embodiments, the second active agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi-modal therapy (e.g. a chemotherapeutic agent and a targeted therapy),Atty. Docket No.0282-0009WO2

[0058] In some embodiments, the “subject” or “subject in need thereof” can refer to a subject whose cancer has recurred or relapsed. For lung cancer patients whose cancer has recurred, this can correspond to a later line treatment setting, such as second, third, fourth, or greater line of treatment, where initial or induction therapy can correspond to treatment with an immunotherapy and / or surgery. For ovarian cancer patients whose cancer has recurred after first line or induction therapy with chemotherapy and / or surgery, such patients can be considered either platinum-sensitive or platinum-resistant. Platinum-sensitivity or platinum resistance is generally based on the time since the last treatment with platinum-based chemotherapeutic agent such as platins, wherein platinum-sensitive cancers recur greater than 6 months after last platinum-based chemotherapeutic agent is administered, and platinum- resistant cancers recur less than 6 months after the last platinum-based chemotherapeutic agent is administered. Thus, e.g., the term “platinum-resistant ovarian carcinoma” when referring to a subject would be a subject that has a recurrence of ovarian cancer less than 6 months after the last treatment with a platinum-based chemotherapeutic agent. Likewise, e.g., the term “platinum-sensitive ovarian carcinoma” when referring to a subject would be a subject that has a recurrence of ovarian cancer greater than 6 months after the last treatment with a platinum-based chemotherapeutic agent. In some embodiments, platinum-sensitive patients who recur in 6 to 12 months are defined as partially platinum-sensitive. In some embodiments, platinum-sensitive patients who recur more than 12 months are defined as fully platinum- sensitive. In some cases, recurrence can be asymptomatic and thus elevation of certain markers (such as elevated CA-125) is sometimes used as an indicator of recurrence, and can also be an indicator as to whether a subject may be diagnosed as platinum-sensitive or platinum-resistant. The time interval for platinum-sensitivity and platinum-resistance may also be influenced by treatment with certain adjuvant or neo-adjuvant therapy or maintenance therapy that may be administered to the patient in conjunction with chemotherapy or following chemotherapy in first line or induction therapy treatment. Thus, in some embodiments, the “subject” or “subject in need thereof” has previously received treatment for cancer (e.g., with one or more chemotherapeutic agents described herein). In some embodiments, the subject is treated with the heterodimeric TCR-anti-CD3 antibody fusion molecule and the second or more active agents described herein in addition to previous treatment. In some embodiments, the subject is treated with the heterodimeric TCR-anti-CD3 antibody fusion molecule and the second or more active agents described in place of previous treatment.Atty. Docket No.0282-0009WO2

[0059] In some embodiments, the platinum-based antineoplastic agent (platins) are chemotherapeutic agents used to treat cancer. In some embodiments, the platin is cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, tetranitrate, phenanthriplatin, pooplatin, or satraplatin. In some embodiments, the platin is cisplatin, carboplatin, or oxaliplatin.

[0060] Current therapies for patients whose cancer has recurred often may not improve with respect to overall survival even with improvement of progression free survival, and may often have negative treatment side effects. While platins are the current preferred therapy for platinum-sensitive ovarian tumors, platins are the drugs of choice for second-line chemotherapy, in combination with other cytotoxic agents. Current therapies for ovarian cancer patients whose cancer has recurred and are platinum-sensitive or platinum-resistant cancers include further chemotherapy, or certain targeted therapies such as bevacizumab or PARP inhibitors, or a combination of bevacizumab and chemotherapy, or a combination of PARP inhibitors and chemotherapy.

[0061] In some embodiments, the subject has serum LDH of between about 1.1 x to about 2.0 x ULN. In some embodiments, the subject is under about 65 years old. In some embodiments, the subject is at least about 65 years old.

[0062] In some embodiments, the subject can have at least one (e.g., at least any of 2, 3, 4, 5, 6, or 7) of the following characteristics: (1) ≥ 18 years of age, inclusive; (2) Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 at start of treatment. (3) HLA- A*02:01-positive (testing by central laboratory); (4) meet tumor PRAME testing requirements (testing by central laboratory); (5) possess a recent biopsy (e.g., performed during screening) or an archival tumor biopsy or an adequate tumor biopsy with high tumor PRAME expression; (6) have an evaluable disease, (at least one target or non-target lesion), and measurable disease (at least one target lesion) according to RECIST v1.1; (7) have a disease that is amenable to biopsy and consent to undergo tumor biopsies during screening and during treatment; (8) documented EGFR exon 19 deletion, exon 21 L858R mutation, or T790M mutation determined by a locally approved diagnostic test and / or (9) have one of the following advanced (metastatic or unresectable) solid tumors: Lung cancer, NSCLC, SCLC, Melanoma, Ovarian carcinoma, includes fallopian tube and primary peritoneal cancers, Uterine carcinoma, Endometrioid carcinoma (endometrial clear cell, endometrial serous carcinoma, and endometrial carcinosarcoma), Triple-negative breast cancer, germ cell tumors (choriocarcinoma, seminoma, and spermatocytic tumors), sarcomas (myxoid liposarcoma,Atty. Docket No.0282-0009WO2 round cell liposarcoma, and synovial sarcoma), adenoid cystic carcinoma, basal cell carcinoma of the skin, thymic carcinoma, peripheral nerve sheath tumor, Merkel cell carcinoma / skin neuroendocrine carcinoma, head and neck squamous cell carcinoma, squamous cervical carcinoma, and urothelial carcinoma. In some embodiments, the subject does not have history or current evidence of brain metastases, including leptomeningeal involvement. In some embodiments, the subject does not have pre-existing peripheral neuropathy of NCI CTCAE Scale of Grade > 2.

[0063] In some embodiments, the subject having non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer has a mutation in BRAF. In some embodiments, the subject has a BRAF V600 mutation. In some embodiments, the subject has a BRAF V600E mutation. In some embodiments, the subject does not comprise a mutation in BRAF (e.g., the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME- positive cancer comprises wild-type BRAF). In some embodiments, the subject does not comprise BRAF mutant such as a BRAF mutant with increased activity (for example, increased kinase activity, and / or increased activity as compared to wild-type BRAF) or a BRAF gain-of-function mutant. In some embodiments, the subject does not comprise a constitutive active BRAF mutant. In some embodiments, the subject does not comprise BRAF V600E mutation (e.g., the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer comprises wild-type BRAF). In some embodiments, the subject comprises wild-type BRAF (e.g., the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer cells have wild-type BRAF). In some embodiments, the subject comprises a BRAF mutant such as a BRAF mutant with increased activity (for example, increased kinase activity, and / or increased activity as compared to wild-type BRAF) or a BRAF gain-of-function mutant. In some embodiments, the subject comprises a constitutive active BRAF mutant.

[0064] In some embodiments, the subject has elevated serum lactate dehydrogenase (“LDH”) level. In some embodiments, the subject has serum LDH of less than about 0.8 χ upper limit of normal (“ULN”). In some embodiments, the subject has serum LDH at about 0.8 χ to about 1.1 x ULN. In some embodiments, the subject has serum LDH of between greater than about 1.1 x to about 2.0 x ULN.

[0065] In some embodiments, the subject can be treated when the subject has pre-cancerous lesions, or when the subject is first diagnosed. In some embodiments, the methods describedAtty. Docket No.0282-0009WO2 herein can be used when the subject has been diagnosed with a life expectancy of greater than 1 year, greater than 6 months, greater than 3 months, or greater than 1 month. In some embodiments, the methods described herein can be used when the subject has been diagnosed with a life expectancy of greater than 3 months. In some embodiments, the methods described herein can be used when the subject has been diagnosed with a life expectancy of less than 5 years, less than 3 years, less than 2 years, less than 1 year, or less than 6 months. The skilled artisan can appreciate that determining “life expectancy” is an estimate that can be determined by skilled artisans using known methods in the art, e.g., age of subject, stage of cancer, thickness and size of tumor, speed of growth, malignancy, contributory factors, etc.

[0066] In some embodiments, the subject is HLA-A*02 positive. The term “HLA-A*02 positive” refers to a subject having TCRs that bind to the SLLQHLIGL(SEQ ID NO: 1)- HLA-A*02 complex. In some embodiments, the subject is HLA-A*02:01 positive. The term “HLA-A*02:01 positive refers to a subject that expresses the HLA-A*02 genotype with the HLA-A*02:01 allele.

[0067] The term “treating” refers to administering an active agent with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition (e.g., a disease), the symptoms of the condition, or to prevent or delay the onset of the symptoms, complications, biochemical indicia of a disease, or otherwise arrest or inhibit further development of the cancer in a statistically significant manner, e.g., a non-small or small cell lung cancer, ovarian carcinoma and / or a subject having a PRAME-positive cancer in a statistically significant manner.

[0068] In some embodiments, the kits and methods described herein are directed to treatment of a cancer, e.g., non-small or small cell lung cancer and / or ovarian carcinoma in a subject, e.g., a subject having a PRAME-positive cancer. However, in some embodiments, the kits and methods described herein can be directed to other PRAME positive subjects. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer is metastatic. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer is metastatic malignant. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME- positive cancer to be treated in the subject is stage 0, stage I, stage II, stage III, or stage IV. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer to be treated is stage 0, stage IA, stage IB, stage IIA, stage IIB, stageAtty. Docket No.0282-0009WO2 IIC, stage IIIA, stage IIIB, stage IIIC, or stage IV. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer to be treated is stage III. In some embodiments, the non-small or small cell lung cancer, ovarian carcinoma and / or a PRAME-positive cancer to be treated is stage IV. In some embodiments, the stage of cancer, e.g., stage IV cancer, is histologically confirmed. Histological confirmation refers to the use of visual means, e.g., microscope, to look at a tissue to determine whether it has signs of the cancer, disease or other abnormalities associated with cancer. In some embodiments, the tissue used in the histological examination has been excised by biopsy or surgical section. Staging of melanoma can be based on a method known to one skilled in the art. Staging of can be determined according to the criteria in the TNM or AJCC staging system (the contents disclosed therein is incorporated by reference in its entirety) created by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). The TNM staging system is used to describe most types of cancer.

[0069] In some embodiments, the disclosure provides a method of treating non-small or small cell lung cancer and / or ovarian carcinoma in a subject (e.g., human) comprising administering to the subject a composition comprising the heterodimeric TCR-anti-CD3 antibody fusion molecule as described herein. In some embodiments, the method of treating small cell lung cancer and / or ovarian carcinoma using TCR-anti-CD3 antibody fusion molecule further comprises a second active agent. In embodiments, the second active agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi-modal therapy (e.g. a chemotherapeutic agent and a targeted therapy),

[0070] In some embodiments, the present disclosure relates to the treatment of PRAME positive cancers. The term "PRAME positive cancer” refers to a PReferentially expressed Antigen in MElanoma (i.e., PRAME) cancer in which at least some of the cancer cells express PRAME. PRAME was first identified as an antigen that is over expressed in melanoma (Ikeda et al Immunity.1997 Feb;6(2):199-208); it is also known as CT130, MAPE, OIP-4 and has Uniprot accession number P78395. The protein functions as a repressor of retinoic acid receptor signaling (Epping et al., “The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling,” Cell 122(6): 835-47 (2005)). PRAME belongs to the family of germline-encoded antigens known as cancer testis antigens. Cancer testis antigens are attractive targets for immunotherapeutic interventionAtty. Docket No.0282-0009WO2 since they typically have limited or no expression in normal adult tissues. PRAME is expressed in a number of solid tumors as well as in leukemias and lymphomas. PRAME targeting therapies of the invention may be particularly suitable for treatment of cancers including, but not limited to, melanoma, lung cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, bladder cancer, head and neck cancer, uterine cancer, Acute myeloid leukemia, chronic myeloid leukemia, and Hodgkin’s lymphoma.

[0071] The peptide SLLQHLIGL (SEQ ID NO: 1) corresponds to amino acids 425-433 of the full length PRAME protein and is presented on the cell surface in complex with HLA- A*02 (Kessler et al., “Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis,” J Exp Med.193(1):73-88 (2001)). This peptide-HLA complex provides a useful target for TCR-based immunotherapeutic intervention.

[0072] WO 2018 / 234319, and corresponding US Pat. Nos.11,427,624 and 11,718,657, describes TCRs that bind to the SLLQHLIGL(SEQ ID NO: 1)-HLA-A*02 complex, each of which is incorporated by reference herein in their entirety. The TCRs are mutated relative to a native PRAME TCR alpha and / or beta variable domains to have improved binding affinities for, and / or binding half-lives, for the complex, and can be associated (covalently or otherwise) with a therapeutic agent. One such therapeutic agent is an anti-CD3 antibody, or a functional fragment or variant of said anti-CD3 antibody such as a single chain variable fragment (scFv). The anti-CD3 antibody or fragment may be covalently linked to the C- or N- terminus of the alpha or beta chain of the TCR. The resulting molecule is a TCR bispecific.

[0073] TCR bispecific proteins redirect polyclonal T cells to target peptides derived from intra- or extra-cellular disease associated antigens and presented on the cell surface in complex with an HLA molecule. This approach has been tested clinically in the context of a different antigen with a TCR bispecific protein targeting an HLA-A*02 restricted peptide from gp100 and CD3 (tebentafusp). Administration of this molecule provided an OS benefit in uveal melanoma (Nathan et al., 2021). However, no such TCR bispecific proteins targeting PRAME have been tested clinically.

[0074] In other words, a PRAME positive cancer is a cancer associated with PRAME expression. In some embodiments, the cancer is known to be associated with expression of PRAME. For example, in some embodiments, the prevalence of PRAME expression isAtty. Docket No.0282-0009WO2 known to be elevated in a cancer and thus PRAME expression is not assessed or is assessed retrospectively. Alternatively, PRAME expression can be assessed using any method known in the art, including, for example, histological methods or other quantitative or qualitative measurements, including PCR, RNA expression analysis, and / or kits or sequence panels designed to measure the expression level of PRAME. However, the disclosure is not intended to be limited to the treatment of cancers for which PRAME expression can be detected by histological methods. In particular, the disclosure is not intended to be limited to the treatment of subject in whom PRAME expression can be detected, for example by histological methods. Rather, the disclosure is useful for the treatment of cancers and tumor types which are considered to be PRAME positive. In some embodiments, a PRAME positive subject can have a cutaneous melanoma. In some embodiments, a PRAME positive subject does not have cutaneous melanoma, but has another typey of PRAME positive cancer. In some embodiments, the PRAME positive cancer, e.g., cutaneous melanoma, can have relapsed from, be refractory to, or be intolerant of standard treatment regimens.

[0075] PRAME expression, when detected by histological methods like immunohistochemistry (IHC), can be quantified using an H-score. Expression of PRAME in subject cells or their sub-cellular compartments within a tumor is first detected and classified as either positive or negative. The positive cells can be further classified into high, medium, or low based on the IHC signal intensity. The H-score captures both the intensity and the proportion of the biomarker of interest from the IHC image and comprises values between 0 and 300, thereby offering a dynamic range to quantify abundance or a particular marker or gene.

[0076] The methods and kits described herein comprise heterodimeric TCR-anti-CD3 antibody fusion molecules. The heterodimeric TCR-anti-CD3 antibody fusion molecules comprise two domains: – a heterodimeric TCR; and – an anti-CD3 antibody.

[0077] Heterodimeric TCR-anti-CD3 antibody fusion molecules are described in, e.g., WO 2023 / 099622, incorporated by reference in its entirety.

[0078] Heterodimeric TCR can comprise a TCR comprising an alpha chain (i.e., TCR alpha chain) and a beta chain (i.e., TCR beta chain). Each chain can comprise variable, joining andAtty. Docket No.0282-0009WO2 constant regions, and the beta chain also usually contains a short diversity region between the variable and joining regions, but this diversity region can be considered as part of the joining region. Each variable region can comprise three CDRs (Complementarity Determining Regions) embedded in a framework sequence, one being the hypervariable region named CDR3. There are several types of alpha chain variable (Vα) regions and several types of beta chain variable (Vβ) regions distinguished by their framework, CDR1 and CDR2 sequences, and by a partly defined CDR3 sequence. The Vα types are referred to in IMGT nomenclature by a unique TRAV number, Vβ types are referred to by a unique TRBV number.

[0079] In some embodiments, the disclosure provides a TCR alpha chain amino acid sequence of SEQ ID NO: 14 or a TCR alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the disclosure provides a TCR beta chain-anti-CD3 amino acid sequence of SEQ ID NO: 16 or a TCR beta chain-anti-CD3 amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the TCR alpha chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the TCR beta chain variable domain comprises CDRs 1 , 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

[0080] In some embodiments, the TCR can bind the sequence SLLQHLIGL (SEQ ID NO: 1). The peptide of SEC ID NO: 1 corresponds to amino acids 425-433 of the full length PRAME protein and is presented on the cell surface in complex with HLA-A*02 (Kessler et al., “Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis,” J Exp Med 193(1):73-88 (2001)). This peptide-HLA complex provides a useful target for TCR-based immunotherapeutic intervention. WO 2018 / 234319 describes TCRs that bind to the SLLQHLIGL(SEQ ID NO: 1)-HLA-A*02 complex and is incorporated herein in its entirety.

[0081] In some embodiments, the heterodimeric TCR is fused with an antibody to CD3 to have improved binding affinities for, and / or binding half-lives. One such antibody is an anti- CD3 antibody, or a functional fragment or variant of said anti-CD3 antibody such as a single chain variable fragment (scFv). The anti-CD3 antibody or fragment may be covalently linkedAtty. Docket No.0282-0009WO2 to the C- or N- terminus of the alpha or beta chain of the TCR. The resulting molecule is a TCR bispecific.

[0082] TCR bispecific proteins redirect polyclonal T cells to target peptides derived from intra- or extra-cellular disease associated antigens and presented on the cell surface in complex with an HLA molecule. This approach has been tested clinically in the context of a different antigen with a TCR bispecific protein targeting an HLA-A*02 restricted peptide from gp100 and CD3 (tebentafusp). Administration of this molecule provided an OS benefit in uveal melanoma (Nathan et al., 2021).

[0083] The term “antibody” includes, but is not limited to, genetically engineered or otherwise modified forms of immunoglobulins, such as intrabodies, chimeric antibodies, fully human antibodies, humanized antibodies (e.g. generated by “CDR-grafting”), antibody fragments, and heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies, tetra-bodies, etc.). The term “antibody” includes cys-diabodies and minibodies. Thus, each and every embodiment provided herein in regard to “antibodies”, or “antibody like constructs” is also envisioned as, bi-specific antibodies, diabodies, scFv fragments, chimeric antibody receptor (CAR) constructs, diabody and / or minibody embodiments, unless explicitly denoted otherwise. The term “antibody” includes a polypeptide of the immunoglobulin family or a polypeptide comprising fragments of an immunoglobulin that is capable of non- covalently, reversibly, and in a specific manner binding a corresponding antigen, as disclosed herein. An exemplary antibody structural unit comprises a tetramer. In some embodiments, a full-length antibody can be composed of two identical pairs of polypeptide chains, each pair having one “light” and one “heavy” chain (connected through a disulfide bond). The term “antibody” also comprises immunoglobulins (Ig's) of different classes (i.e., IgA, IgG, IgM, IgD and IgE) and subclasses (such as IgG1, IgG2 etc.).

[0084] The terms "anti-CD3 antibody" and "anti-CD3 antibody fragment," as used herein, mean antibodies or antibody fragments which recognize or bind to CD3.The TCR-anti-CD3 fusion molecule for use in the present disclosure can include one or more conservative substitutions which have a similar amino acid sequence and / or which retain the same function (i.e. are phenotypically silent as defined above). The skilled person is aware that various amino acids have similar properties and thus substitutions between them are “conservative”. One or more such amino acids of a protein, polypeptide or peptide can often be substituted byAtty. Docket No.0282-0009WO2 one or more other such amino acids without eliminating a desired activity of that protein, polypeptide, or peptide.

[0085] In some embodiments, the TCR-anti-CD3 fusion molecule for use in the invention comprises an anti-CD3 scFv covalently linked to the N-terminus of the beta chain of a TCR via a linker. This type of molecule is known as an ImmTAC® (Immune Mobilizing Monoclonal TCRs Against Cancer). ImmTAC® molecules are engineered to activate a potent T cell response to specifically kill target cancer cells. In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecules for use in the invention are ImmTAC molecules (i.e., ImmTACs targeting PRAME) as described in WO 2018 / 234319, which is incorporated by reference herein in its entirety.

[0086] In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecules is IMC-F106C. IMC-F106C is a T cell redirecting bispecific therapeutic agent comprising a soluble affinity enhanced TCR that binds to the SLLQHLIGL(SEQ ID NO: 1) peptide-HLA- A*02 complex, fused to an anti-CD3 scFv. The targeting end of IMC-F106C (the soluble TCR) binds to a peptide fragment of the PRAME antigen presented by HLA-A*02 on the surface of cancer cells. HLA molecules are polymorphic; approximately 47% of Caucasian individuals in the US and European countries express the HLA-A*02 genotype with the HLA-A*02:01 allele detected in more than 95% of HLA-A*02-positive individuals. The effector end of IMC-F106C (anti-CD3 scFv) can bind to CD3 on any T cell, redirecting the T cell to produce effector cytokines and / or kill the cell presenting the target. In addition, IMC- F106C-mediated tumor lysis may prime an endogenous anti-tumor immune response. ImmTAC® (Immune Mobilizing Monoclonal TCRs Against Cancer) molecules such as IMC-F106C are highly potent molecules, with redirection of T-cell activity observed against tumor cell lines presenting as few as 10 to 50 target peptide:HLA complexes. IMC-F106C has been shown to selectively redirect T cell activity in the presence of HLA-A*02:01- positive / PRAME-positive cell lines, leading to T cell activation and killing of PRAME- positive cancer cells, at concentrations as low as 1 pM to 10 pM. As described above, the HLA-A*02 restricted peptide SLLQHLIGL (SEQ ID NO: 1) is derived from the germline cancer antigen PRAME. IMC-F106C has a TCR alpha chain amino acid sequence of SEQ ID NO: 14 and a TCR beta chain-anti-CD3 amino acid sequence of SEQ ID NO: 16.

[0087] PRAME is a cancer-testis antigen that is frequently highly expressed in a range of solid and hematologic malignancies including melanoma, ovarian carcinoma, uterineAtty. Docket No.0282-0009WO2 carcinoma, small-cell and non-small cell lung cancer, triple-negative breast cancer, and several rare tumor types.

[0088] The sequences referred to herein are as follows:

[0089] SEQ ID NO: 1 HLA-A*02 restricted peptide: SLLQHLIGL

[0090] SEQ ID NO: 2 Amino acid sequence of the TCR alpha chain variable domain of the ImmTAC designated as IMC-F106C. CDRs (CDR1 , CDR2 and CDR3) are underlined and are designated SEQ ID NO: 3, 4 and 5 respectively, framework regions (FR1 , FR2, FR3 and FR4) are in italics and are designated SEQ ID NO: 27, 6, 7 and 28 respectively. Mutations with respect to native alpha chain are in bold.

[0091] GDAKTTQPNSMESNEEEPVHLPCNHSTISGTDYIHWYRQLPSQGPEYVIHGLTS NVNNRMASLAIAEDRKSSTLILHRATLRDAAVYYCILILGHSRLGNYIATFGKGTKLSVIP

[0092] SEQ ID NO: 8 Amino acid sequence of the TCR beta chain variable domain of the ImmTAC designated as IMC-F106C. CDRs (CDR1 , CDR2 and CDR3) are underlined and are designated SEQ ID NO: 9, 10 and 11 respectively, framework regions (FR1, FR2, FR3 and FR4) are in italics and are designated SEQ ID NO: 29, 12, 13 and 30 respectively. Mutations with respect to native beta chain are in bold.

[0093] DGGITQSPKYLFRKEGQNVTLSCEQNLNHDAMYWYRQDPGQGLRLIYYSQIMG DEQKGDIAEGYSVSREKKESFPLTVTSAQKNPTAFYLCASSWWTGGASPIRFGPGTRLT VT

[0094] SEQ ID NO: 14 Amino acid sequence of the TCR alpha chain of the ImmTAC designated as IMC-F106C. CDRs (CDR1, CDR2 and CDR3) are underlined and are designated SEQ ID NO: 3, 4 and 5 respectively, framework regions (FR1 , FR2, FR3 and FR4) are in italics and are designated SEQ ID NO: 27, 6, 7 and 28 respectively. The constant region is shown in bold and is designated SEQ ID NO: 15. Within the constant region, the nonnative cysteine residue is double underlined (at position 48 of constant region).

[0095] GDAKTTQPNSMESNEEEPVHLPCNHSTISGTDYIHWYRQLPSQGPEYVIHGLTS NVNNRMASLAIAEDRKSSTLILHRATLRDAAVYYCILILGHSRLGNYIATFGKGTKLSVIPNI QNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMD FKSNSAVAWSNKSDFACANAFNNSIIPEDTAtty. Docket No.0282-0009WO2

[0096] SEQ ID NO: 16 Amino acid sequence of the TCR beta chain-anti-CD3 of the ImmTAC designated as IMC-F106C. Anti-CD3 scFv (amino acids 1-253) is shown in bold and underline and is designated SEQ ID NO: 17. The linker (GGGGS) appears immediately after the scFv, is shown in paler text and is designated SEQ ID NO: 18. CDRs (CDR1 , CDR2 and CDR3) are underlined and are designated SEQ ID NO: 9, 10 and 11 respectively, framework regions (FR1, FR2, FR3 and FR4) are in italics and are designated SEQ ID NO: 29, 12, 13 and 30 respectively. Constant region is shown in bold (no underline) and is designated SEQ ID NO: 19. Within the constant region, the nonnative cysteine residue is double underlined (at position 57 of constant region). Additional non-native amino acids at position 75 and position 89 of the constant region are also double underlined.

[0097] AIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIY YTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKV EIKGGGGSGGGGSGGGGSGGGGSGGGSEVQLVESGGGLVQPGGSLRLSCAASG YSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTA YLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDGGIT QSPKYLFRKEGQNVTLSCEQNLNHDAMYWYRQDPGQGLRLIYYSQIMGDEQKGDIAEG YSVSREKKESFPLTVTSAQKNPTAFYLCASSWWTGGASPIRFGPGTRLTVTEDLKNVFPP EVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQP LKEQPALNDSRYALSSRLRVSATFWQDPRNHFRCQVQFYGLSENDEWTQDRAK PVTQIVSAEAWGRAD

[0098] CDR sequences of the ImmTAC designated as IMC-F106C as follows: Alpha Alpha chain Alpha chain Beta chain Beta chain Beta chain chain CDR2 CDR3 CDR1 CDR2 CDR3 CDR1 TISGTDY GLTSN CILILGHSR LNHDA SQIMGDE CASSWWT (SEQ ID (SEQ ID LGNYIATF (SEQ ID (SEQ ID GGASPIRF NO:3) NO: 4) (SEQ ID NO: 9) NO: 10) (SEQ ID NO: 5) NO: 11)Atty. Docket No.0282-0009WO2

[0099] Framework region sequences of the ImmTAC designated as IMC-F106C: Alpha chain FR1 Alpha chain Alpha chain FR3 Alpha chain FR4 FR2 GDAKTTQPNSMES IHWYRQLP VNNRMASLAIA GKGTKLSVIP NEEEPVHLPCNHS SQGPEYVIH EDRKSSTLILHR (SEQ ID NO: 28) (SEQ ID NO:27) (SEQ ID NO: 6) ATLRDAAVYY (SEQ ID NO: 7) Beta chain FR1 Beta chain FR2 Beta chain FR3 Beta chain FR4 DGGITQSPKYLFRK MYWYRQDP QKGDIAEGYSV GPGTRLTVT EGQNVTLSCEQN GQGLRLIYY SREKKESFPLTV (SEQ ID NO: 30) (SEQ ID NO:29) (SEQ ID NO: TSAQKNPTAFYL 12) (SEQ ID NO: 13)

[0100] Additional linker sequences referred to herein:

[0101] GGGSG (SEQ ID NO: 20), GGSGG (SEQ ID NO: 21), GSGGG (SEQ ID NO: 22), GSGGGP (SEQ ID NO: 23), GGEPS (SEQ ID NO: 24), GGEGGGP (SEQ ID NO: 25), and GGEGGGSEGGGS (SEQ ID NO: 26)

[0102] In some embodiments, the TCR-anti-CD3 fusion molecule for use in the methods herein comprises: a TCR alpha chain amino acid sequence of SEQ ID NO: 14 or a TCR alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and a TCR beta chain-anti-CD3 amino acid sequence of SEQ ID NO: 16 or a TCR beta chain-anti-CD3 amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the TCR alpha chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the TOR beta chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

[0103] In other words, although the molecule may have some variation in the TCR alpha chain amino acid sequence compared to the sequence of SEQ ID NO: 14 (as long as the TCR alpha chain amino acid sequence has at least 90% identity to SEQ ID NO: 14) and / or some variation in the TCR beta chain-anti-CD3 amino acid sequence compared to the sequence ofAtty. Docket No.0282-0009WO2 SEQ ID NO: 16 (as long as the TCR beta chain-anti-CD3 amino acid sequence has at least 90% identity to the amino acid sequence of SEQ ID NO: 16), the CDRs of the TCR alpha chain must have the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the CDRs of TCR beta chain must have the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively. The requirement for the TCR alpha chain variable domain to comprise CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the requirement for the TCR beta chain variable domain to comprise CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively thus applies to all aspects and embodiments of the invention described herein. The TCR alpha chain variable domain thus comprises CDRs 1, 2 and 3 having 100% identity to the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the TCR beta chain variable domain comprises CDRs 1, 2 and 3 having 100% identity to the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

[0104] In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule is IMC-F106C. Within the scope of the present disclosure are phenotypically silent variants of the TCR-anti-CD3 fusion molecule designated as IMC-F106C, which has a TCR alpha chain amino acid sequence corresponding to SEQ ID NO: 14 and a TCR beta chain-anti-CD3 amino acid sequence corresponding to SEQ ID NO: 16. As used herein the term “phenotypically silent variant” is understood to refer to a TCR-anti-CD3 fusion molecule which incorporates one or more further amino acid changes, including substitutions, insertions and deletions, compared to the sequences of SEQ ID NO: 14 and SEQ ID NO: 16 and which TCR-anti-CD3 fusion molecule has a similar phenotype to or the same phenotype as the TCR-anti-CD3 fusion molecule designated as IMC-F106C. For the purposes of this application, TCR-anti-CD3 fusion molecule phenotype comprises antigen binding affinity (KD and / or binding half-life) and antigen specificity. A phenotypically silent variant may have a KD and / or binding half-life for the SLLQHLIGL (SEQ ID NO: 1) HLA-A*02 complex within 50%, or more preferably within 20%, of the measured KD and / or binding half-life of the TCR-anti-CD3 fusion molecule designated as IMC-F106C, when measured under identical conditions (for example at 25 °C and / or on the same SPR chip). Suitable conditions are further provided in Example 3 of WQ / 2018 / 234319, which is incorporated herein by reference. Antigen specificity is further defined below. As is known to those skilled in the art, it may be possible to produce TCRs that incorporate changes in the variable domains thereof compared to those detailed above without altering the affinity of theAtty. Docket No.0282-0009WO2 interaction with the SLLQHLIGL (SEQ ID NO: 1) HLA-A*02 complex. In particular, such silent mutations may be incorporated within parts of the sequence that are known not to be directly involved in antigen binding. Such trivial variants are included in the scope of this invention.

[0105] Phenotypically silent variants may contain one or more conservative substitutions and / or one or more tolerated substitutions. Tolerated and conservative substitutions may result in a change in the KD and / or binding half-life for the SLLQHLIGL (SEQ ID NO: 1) HLA-A*02 complex within 50%, or more preferably within 20%, even more preferably within 10%, of the measured KD and / or binding half-life of the TCR-anti-CD3 fusion molecule designated as IMC-F106C, when measured under identical conditions (for example at 25°C and / or the same SPR chip), provided that the change in KD does not result in the affinity being less than (i.e. weaker than) 200 pM. By tolerated substitutions it is meant those substitutions which do not fall under the definition of conservative as provided below but are nonetheless phenotypically silent.

[0106] The TCR-anti-CD3 fusion molecule for use in the methods described herein can include one or more conservative substitutions which have a similar amino acid sequence and / or which retain the same function (i.e., are phenotypically silent as defined above). The skilled person is aware that various amino acids have similar properties and thus substitutions between them are “conservative”. One or more such amino acids of a protein, polypeptide or peptide can often be substituted by one or more other such amino acids without eliminating a desired activity of that protein, polypeptide, or peptide.

[0107] Thus, the amino acids glycine, alanine, valine, leucine, and isoleucine can often be substituted for one another (amino acids having aliphatic side chains). Of these possible substitutions it is preferred that glycine and alanine are used to substitute for one another (since they have relatively short side chains) and that valine, leucine and isoleucine are used to substitute for one another (since they have larger aliphatic side chains which are hydrophobic). Other amino acids which can often be substituted for one another include: phenylalanine, tyrosine and tryptophan (amino acids having aromatic side chains); lysine, arginine and histidine (amino acids having basic side chains); aspartate and glutamate (amino acids having acidic side chains); asparagine and glutamine (amino acids having amide side chains); and cysteine and methionine (amino acids having Sulphur containing side chains). It should be appreciated that amino acid substitutions within the scope of the present inventionAtty. Docket No.0282-0009WO2 can be made using naturally occurring or non-naturally occurring amino acids. For example, it is contemplated herein that the methyl group on an alanine may be replaced with an ethyl group, and / or that minor changes may be made to the peptide backbone. Whether or not natural or synthetic amino acids are used, it is preferred that only L- amino acids are present.

[0108] Substitutions of this nature are often referred to as “conservative” or “semi- conservative” amino acid substitutions. The present invention therefore extends to use of a TCR-anti-CD3 fusion molecule comprising an amino acid sequence described above but with one or more conservative substitutions and / or one or more tolerated substitutions in the sequence, such that the TCR alpha chain amino acid sequence has at least 90% identity (such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity) to the amino acid sequence of SEQ ID NO: 14, and the TCR beta chain-anti-CD3 amino acid sequence has at least 90% identity (such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity) to the amino acid sequence of SEQ ID NO: 16, and provided that the TCR alpha chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the TCR beta chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

[0109] “Identity” as known in the art is the relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as the case can be, as determined by the match between strings of such sequences. While there exist a number of methods to measure identity between two polypeptide or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs. Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et al., “A comprehensive set of sequence analysis programs for the VAX,” Nucleic Acids Research, 12, 387-95 (1984)), BLASTP, BLASTN, and FASTA (Atschul et al., “Basic local alignment search tool,” J. Molec. Biol.215(3), 403-10 (1990)).

[0110] One can use a program such as the CLUSTAL program to compare amino acid sequences. This program compares amino acid sequences and finds the optimal alignment by inserting spaces in either sequence as appropriate. It is possible to calculate amino acid identity or similarity (identity plus conservation of amino acid type) for an optimal alignment. A program like BLASTx will align the longest stretch of similar sequences and assign a valueAtty. Docket No.0282-0009WO2 to the fit. It is thus possible to obtain a comparison where several regions of similarity are found, each having a different score. Both types of identity analysis are contemplated in the present disclosure.

[0111] The percent identity of two amino acid sequences or of two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence for best alignment with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions. The “best alignment” is an alignment of two sequences which results in the highest percent identity. The percent identity is determined by the number of identical amino acid residues or nucleotides in the sequences being compared (i.e., % identity = number of identical positions / total number of positions x 100).

[0112] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm known to those of skill in the art. An example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. The NBLAST and XBLAST programs of Altschul, et al. (1990) J. Mol. Biol.215:403-410 have incorporated such an algorithm. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to nucleic acid molecules. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules for use in the disclosure. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res.25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI- Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http: / / www.ncbi.nlm.nih.gov. Another example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). The ALIGN program (version 2.0) which is part of the CGC sequence alignment software package has incorporated such an algorithm. Other algorithms for sequence analysis known in the art include ADVANCE and ADAM as described in Torellis and Robotti (1994) Comput. Appl. Biosci., 10 :3-5; and FASTA described in PearsonAtty. Docket No.0282-0009WO2 and Lipman (1988) Proc. Natl. Acad. Sci.85:2444-8. Within FASTA, ktup is a control option that sets the sensitivity and speed of the search.

[0113] Mutations, including conservation and tolerated substitutions, insertions, and deletions, can be introduced into the sequences provided using any appropriate method including, but not limited to, those based on polymerase chain reaction (PCR), restriction enzyme-based cloning, or ligation independent cloning (LIC) procedures. These methods are detailed in many of the standard molecular biology texts. For further details regarding polymerase chain reaction (PCR) and restriction enzyme-based cloning, see Sambrook & Russell, (2001) Molecular Cloning - A Laboratory Manual (3rdEd.) CSHL Press. Further information on ligation independent cloning (LIC) procedures can be found in Rashtchian, (1995) Curr Opin Biotechnol 6(1): 30-6. The TCR sequences provided by the disclosure can be obtained from solid state synthesis, or any other appropriate method known in the art.

[0114] The TCR-anti-CD3 fusion molecules for use in the present disclosure have the property of binding the SLLQHLIGL (SEQ ID NO: 1) HLA-A*02 complex. TCR-anti-CD3 fusion molecules for use in the present disclosure have been found to strongly recognize this epitope relative to other, irrelevant epitopes, and are thus particularly suitable as targeting vectors for delivery of therapeutic agents or detectable labels to cells and tissues displaying those epitopes. Specificity in the context of TCR-anti-CD3 fusion molecule for use in the present disclosure relates to their ability to recognize HLA-A*02 target cells that are antigen positive, whilst having minimal ability to recognize HLA-A*02 target cells that are antigen negative.

[0115] The method of the present disclosure is a dose escalation regimen, in which increasing doses of the heterodimeric TCR-anti-CD3 fusion molecule are sequentially administered to the subject. Doses are thus administered in the specified order: first dose, then second dose, then maintenance dose. "First dose" refers to a dose, i.e., dosage amount, of the TCR-anti-CD3 fusion molecule at a first amount within the specified range. "Second dose" refers to a dose, i.e., dosage amount, of the TCR-anti-CD3 fusion molecule at a second amount within the specified range, which is greater than the first dose. "Maintenance dose" refers to a dose, i.e., dosage amount, of the TCR-anti-CD3 fusion molecule at a maintenance amount within the specified range, which is greater than the second dose. It will be appreciated that according to the method of the present disclosure, a subject will receive at least three total doses (i.e., a first dose, a second dose, and a maintenance dose). However, inAtty. Docket No.0282-0009WO2 some embodiments, the subject can receive more than three total doses, as the subject can receive one or more first doses, one or more second doses, and one or more maintenance doses of the heterodimeric TCR-anti-CD3 antibody fusion molecule. As used herein, the amount in each second dose is larger than the amount in each first dose, and the amount in each maintenance dose is larger than the amount in each second dose.

[0116] In the present disclosure, each dose (i.e., first dose, second dose, maintenance) are expressed as a specified mass, i.e., weight, of the heterodimeric TCR-anti-CD3 antibody fusion molecule. Other vehicles, excipients, carriers, etc., may be administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule but are not included in the calculated mass.

[0117] In some embodiments, the first dose is about 2 µg to about 30 µg. In some embodiments, the first dose is about 2 µg to about 20 µg, about 2 µg to about 10 µg, about 2 µg to about 5 µg or about 2.5 to about 3.5 µg. In some embodiments, the first dose is about 3 µg. In some embodiments, the first dose is about 5 µg to about 25 µg, about 10 µg to about 24 µg, about 15 µg to about 23 µg or about 18 to about 22 µg. In some embodiments, the first dose is about 20 µg. The dose can be 2 µg, 3 µg, 4 µg, 5 µg, 6 µg, 7 µg, 8 µg, 9 µg, 10 µg, 11 µg, 12 µg, 13 µg, 14 µg, 15 µg, 16 µg, 17 µg, 18 µg, 19 µg, 20 µg, 21 µg, 22 µg, 23 µg, 24 µg, 25 µg µg, 26 µg, 27 µg, 28 µg, 29 µg or 30 µg. In some embodiments, the first dose is 3 µg, 10 µg or 20 µg. In some embodiments, the first dose is 3 µg. In some embodiments, the first dose is 20 µg.

[0118] Various numbers of first doses can be administered to the subject. For example, in some embodiments, the first dose is administered once, i.e., one time. In some embodiments, the first dose is administered more than one time, e.g., two to 10 times, two to five times, or two to three times. In some embodiments, the first dose is administered two times.

[0119] The number of first doses can be determined, for example, by the occurrence or severity of an adverse event (AE) following administration of the first dose. In cases with adverse events, the method can include administration of more than one first doses before escalating to the second dose. In some embodiments, the first dose is a “range” of amounts, e.g., 2 to 30 µg. Thus, in some embodiments wherein multiple first doses are administered, the first dose can comprise the same amount in each first dose (e.g., each first dose comprises 2 µg). In some embodiments wherein multiple first doses are administered, the first doseAtty. Docket No.0282-0009WO2 amount can comprise different amounts in one or more of each first dose (e.g., first dose #1 comprises 2 µg and first dose #2 comprises 4 µg), as long as each dose is within the first dose amount specified.

[0120] In some embodiments, the second dose is about 5 µg to about 60 µg. In some embodiments, the second dose is about 5 µg to about 60 µg, about 6 to about 30 µg, about 7 µg to about 20 µg, about 8 µg to about 15 µg or about 8 µg to about 12 µg. In some embodiments, the second dose is about 10 µg. In some embodiments, the second dose is about 10 µg to about 60 µg, about 20 µg to about55 µg, about 30 µg to about 50 µg, about 35 µg to about 45 µg or about 38 µg to about 42 µg. In some embodiments, the second dose is about 40 µg. The second dose can be 5 µg, 10 µg, 15 µg, 20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, 55 µg, or 60 µg. In some embodiments, the second dose is about 10 µg, 20 µg, 40 µg, or 60 µg. In some embodiments, the second dose is 10 µg. In some embodiments, the second dose is 40 µg.

[0121] Various numbers of second doses can be administered to the subject. For example, in some embodiments, the second dose is administered once, i.e., one time. In some embodiments, the second dose is administered more than one time, e.g., two to 10 times, two to five times, or two to three times. In some embodiments, the second dose is administered two times.

[0122] In some embodiments the method can include administration of more than one second dose before escalating to the maintenance dose. In some embodiments, the second dose is a “range” of amounts, e.g., 5 to 60 µg. Thus, in some embodiments wherein multiple second doses are administered, the second dose can comprise the same amount in each second dose (e.g., each second dose comprises 10 µg). In some embodiments wherein multiple second doses are administered, the second dose amount can comprise different amounts in one or more of each second dose (e.g., second dose #1 comprises 10 µg and second dose #2 comprises 15 µg), as long as each dose is within the second dose amount specified.

[0123] The term “maintenance dose(s)” a dosage administered to the subject to maintain the desired therapeutic effect. In some embodiments, the maintenance dose is administered repeatedly until treatment is stopped.Atty. Docket No.0282-0009WO2

[0124] In some embodiments, the maintenance dose is about 15 µg to about 200 µg. In some embodiments, the maintenance dose is about 20 µg to about 100 µg, about 25 to about 50 µg, about 30 µg to about 45 µg, about 35 µg to about 45 µg or about 38 µg to about 42 µg. In some embodiments, the maintenance dose is about 40 µg. In some embodiments, the maintenance dose is about 100 µg to about 200 µg, about 120 µg to about 180 µg, about 150 µg to about 170 µg, about 155 µg to about 165 µg or about 158 µg to about 1622 µg. In some embodiments, the maintenance dose is about 160 µg. The maintenance dose can be 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, 55 µg, 60 µg, 120 µg, 130 µg, 140 µg, 150 µg, 160 µg, 170 µg or 180 µg. In some embodiments, the maintenance dose is about 40 µg, 50 µg, 150 µg, or 160 µg. In some embodiments, the maintenance dose is 20 µg. At 20 µg or greater, Applicant observed durable partial responses (PRs) across several solid tumors including cutaneous melanoma (CM), uveal melanoma (UM), and ovarian carcinoma. In some embodiments, the maintenance dose is 40 µg. In some embodiments, the maintenance dose is 160 µg. Applicant observed that 160 µg was 1) the lowest dose where exposure was detected throughout the dosing period, and 2) compared to the next higher dose tested (320 µg), 160 µg has a lower incidence of cytokine release syndrome (CRS) and requires less dexamethasone premedication.

[0125] Various numbers of maintenance doses can be administered to the subject. For example, in some embodiments, the maintenance dose is administered three times, e.g., one time in each of the three specified phases. In some embodiments, maintenance dose is administered more than one time, e.g., three to 200 times, 10 to 150 times, or 30 to 80 times. In some embodiments, the maintenance dose is administered 30 to 34 times, e.g., 32 times. In some embodiments, the maintenance dose is administered until the melanoma, e.g., cutaneous melanoma, is cured, in remission, or is as otherwise determined by a healthcare professional. Treatment can be stopped, for example due to unacceptable toxicity or the occurrence of adverse events, or because the subject has shown an unacceptable level of disease progression. Alternatively, treatment can be stopped, for example, because the subject's symptoms have reduced in severity and / or tumor has shrunk to a level at which treatment with the TCR-anti-CD3 fusion molecule is deemed no longer necessary.

[0126] In some embodiments the method can include administration of more than one maintenance dose. In some embodiments, the maintenance dose is a “range” of amounts, e.g., 40 to 160 µg. Thus, in some embodiments wherein multiple maintenance doses areAtty. Docket No.0282-0009WO2 administered, the maintenance dose can comprise the same amount in each maintenance dose (e.g., each maintenance dose comprises 40 µg). In some embodiments, the maintenance dose amount can comprise different amounts in one or more of each maintenance dose (e.g., maintenance dose #1 comprises 10 µg and maintenance dose #2 comprises 15 µg), as long as each dose is within the maintenance dose amount specified.

[0127] The methods of the present disclosure provide a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered in specified amount. In some embodiments, when the first dose is administered multiple times, the first dose is administered every 4 days to every 14 days, or every 6 days to every 8 days, until each of the first doses is administered. In some embodiments, when the first dose is administered multiple times, the first dose is administered every 7 days until each of the first doses is administered.

[0128] In some embodiments, when the second dose is administered multiple times, the second dose is administered every 4 days to every 14 days, or every 6 days to every 8 days, until each of the second doses is administered. In some embodiments, when the second dose is administered multiple times, the second dose is administered every 7 days until each of the second doses is administered. In some embodiments, the second dose is administered 4 to 14, or 6 to 8 days after the last administration of the first dose. In some embodiments, the second dose is administered 7 days after the last administration of the first dose.

[0129] In some embodiments, the maintenance dose is first administered 7 days after the last administration of the second dose. The maintenance dose can be administered in three phases, a first phase, a second phase and a third phase. As used herein, the term “phase” refers to a period of time in which the frequency of administration of the maintenance dose is substantially consistent. The term “substantially consistent” refers to a frequency that is ±24 hours of a given value. For example, if the phase frequency was “every 7 days,” then a frequency of 7 days ±24 hours would be in the same phase. In some embodiments, the “first phase” can comprise administering the maintenance dose every 6 to 8 days, the “second phase” can comprise administering the maintenance dose every 12 to 16 days, and / or the “third phase” can comprise administering the maintenance dose every 26 to 30 days. In some embodiments, the “first phase” can comprise administering the maintenance dose every 7 days, i.e., once a week, the “second phase” can comprise administering the maintenance doseAtty. Docket No.0282-0009WO2 every 14 days, i.e., every 2 weeks, and / or the “third phase” can comprise administering the maintenance dose every 28 days, i.e., every 4 weeks.

[0130] While not being bound by any particular theory, in some embodiments reducing the frequency from first phase to the second phase, and from second phase to the third phase of the maintenance dose can result in reduced number of side effects, reduced severity of side effects, and high patient compliance. In some embodiments, reducing the frequency from first phase to the second phase, and from second phase to the third phase of the maintenance dose does not reduce the efficacy of the heterodimeric TCR-anti-CD3 antibody fusions molecule. Reducing the frequency of the second and third phases (relative to the first and second phase, respectfully) can reduce overall costs and reduce the time needed for treatment of both the subject and the medical professional administering the treatment.

[0131] In some embodiments, the duration of the first phase of the maintenance dose is about one week to about 20 weeks, or about 4 weeks to about 15 weeks, or about 8 weeks to about 12 weeks. In some embodiments, the duration of the first phase of the maintenance dose is about 10 weeks. In some embodiments, the duration of the second phase of the maintenance dose is about 4 weeks to about 40 weeks, or about 10 weeks to about 30 weeks, or about 16 weeks to about 24 weeks. In some embodiments, the duration of the second phase of the maintenance dose is about 20 weeks. In some embodiments, the duration of the third phase of the maintenance dose is about 10 weeks to about 80 weeks, or about 40 weeks to about 60 weeks, or about 48 weeks to about 54 weeks. In some embodiments, the third phase of the maintenance dose is about 40 weeks to about 60 weeks. In some embodiments, the third phase of the maintenance dose is about 48 weeks.

[0132] In some embodiments, the first phase is 8 weeks to about 14 weeks, the second phase is about 30 weeks to about 50 weeks, and the maintenance phase is about 40 weeks to about 60 weeks. In some embodiments, the first phase is about 10 weeks, the second phase is about 38 weeks, and / or the maintenance phase is about 48 weeks.

[0133] In some embodiments, the dosage regimen, including administration of the first dose, the second dose and the maintenance dose (all three phases), is at least 50 weeks, at least 60 weeks, at least 70 weeks, at least 80 weeks, or at least 90 weeks. In some embodiments, the dosage regimen, including administration of the first dose, the second dose and the maintenance dose (all three phases), is about 90 weeks to about 110 weeks. In someAtty. Docket No.0282-0009WO2 embodiments, the dosage regimen, including administration of the first dose, the second dose and the maintenance dose (all three phases), is about 100 weeks to about 105 weeks. In some embodiments, the dosage regimen, including administration of the first dose, the second dose and the maintenance dose (all three phases), is about 101 weeks.

[0134] In some embodiments, the first dose is administered for 1 to 2 weeks, the second dose is administered for 1 to 2 weeks, and the maintenance dose is administered for at least 40 weeks, e.g., 40 weeks to 156 weeks, 80 weeks to 120 weeks, or 100 weeks to 104 weeks. In some embodiments, the first dose is administered for 1 week, the second dose is administered for 1 week, and the maintenance dose is administered for at least 40 weeks.

[0135] In some embodiments, the present disclosure provides a low dose regimen, wherein the first dose is about 2 to 4 µg, the second dose is about 5 to14 µg, and the maintenance dose is about 15 to 55 µg. Examples of these low dose regimens can be found in FIG.7.

[0136] In some embodiments, the present disclosure provides a high dose regimen, wherein the first dose is about 15 to 40 µg, the second dose is about 30 to 80 µg, and the maintenance dose is about 140 to 200 µg. Examples of these low dose regimens can be found in FIG.8.

[0137] In some embodiments, the methods described herein are a first line treatment. The term “first line treatment” refers to the initial, or first treatment recommended for a disease or illness, e.g., lung or ovarian cancer. In some embodiments, this can also be referred to as primary treatment, initial treatment, or induction therapy. In some embodiments, the first line treatment can include a combination treatment, e.g., treatment with another method, e.g., another active agent and / or surgery.

[0138] In some embodiments, the methods described herein are a second line treatment. In some embodiments, the methods described herein are third line, fourth line, fifth line, sixth line, etc. treatment. Second line or further lines of therapy (third line, fourth line, seventh line, etc.) may be used for a few different reasons, e.g., the first-line treatment doesn't work, the first-line treatment worked but has since stopped working, the first-line treatment has side effects that are not tolerated, and / or new treatment becomes available that appears to be more effective than the present treatment.

[0139] In some embodiments, the methods described herein are for ovarian cancer patients who have recurred after first line or induction therapy (e.g., with chemotherapy) and areAtty. Docket No.0282-0009WO2 either platinum-sensitive or platinum-resistant ovarian cancer patients. In such patients, in some embodiments, the methods comprise treatment of platinum-sensitive or platinum resistant ovarian cancer patients with administration of the TCR-anti-CD3 antibody fusion molecule (such as a TCR-anti-CD3 antibody fusion molecule targeting PRAME, where such molecule corresponds, for example, to IMC-F106C), in combination with a chemotherapeutic agent or a targeted therapy. In some embodiments, the IMC-F106C comprises:

[0140] a TCR alpha chain amino acid sequence of SEQ ID NO: 14 or a TCR alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and

[0141] a TCR beta chain-anti-CD3 amino acid sequence of SEQ ID NO: 16 or a TCR beta chain-anti-CD3 amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16,

[0142] wherein the TCR alpha chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the TOR beta chain variable domain comprises CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

[0143] In some embodiments, the methods described herein are a first line mono-therapy treatment, i.e., the only active agent used for the treatment of the cutaneous melanoma is the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, no corticosteroids are administered before administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, no corticosteroids are administered 3 months, 2 months, 1 month, 3 weeks, 2 weeks or 1 week before administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, no corticosteroids are administered 3 weeks before administration of the heterodimeric TCR- anti-CD3 antibody fusion molecule.

[0144] In some embodiments, the method described herein is a bi-therapy, e.g., a first line treatment bi-therapy wherein a second active agent is co-administered during the dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule is the first active agent. In some embodiments, the methods described herein are a bi-therapy, e.g., a first line treatment bi-therapy, wherein a second active agent, e.g., anti-cancer drug, is co- administered 3 months, 2 months, 1 month, 3 weeks, 2 weeks or 1 week beforeAtty. Docket No.0282-0009WO2 administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the methods described herein are a bi-therapy, e.g., a first line treatment bi- therapy, wherein a second-active agent, e.g., anti-cancer drug, is co-administered 3 months, 2 months, 1 month, 3 weeks, 2 weeks or 1 week after completion of the dosage regimen. In embodiments, the second active agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi-modal therapy (e.g. a chemotherapeutic agent and a targeted therapy),

[0145] In some embodiments, the methods described herein are not a monotherapy, i.e., the method comprises administering the heterodimeric TCR-anti-CD3 antibody fusion molecule and one or more additional active agents, e.g., anti-cancer therapeutic agents.

[0146] In some embodiments, the second TCR-anti-CD3 antibody fusion molecule comprises tebentafusp. In some embodiments the second TCR-anti-CD3 antibody fusion molecule is administered in a first, second and third phase. In some embodiments the second TCR-anti-CD3 antibody fusion molecule is administered in an ascending dose regimen identical or similar to the regimen disclosed herein of the first heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the second TCR-anti-CD3 antibody fusion molecule comprises Tebentafusp administered at 20 mcg on week one, 30 mcg on week two, and 68 mcg weekly on week three and thereafter.

[0147] In some embodiments, the disclosure provides administering the heterodimeric TCR-anti-CD3 antibody fusion molecule described herein with a second active agent (wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule is considered herein as the first active agent). The terms “active” and “therapeutic” agents are used interchangeably throughout the application. In some embodiments, the disclosure provides a dosing regimen further comprising administering a third active agent, a fourth active agent, or greater than four active agents. In some embodiments, the dosing regimen comprises administering a second active agent. In some embodiments, the second active agent, a third active agent, a fourth active agent, or greater than four active agents can be an anti-cancer therapeutic agent. While not being bound by any particular theory, the disclosure provides that in some embodiments, administration of a second active agent can enhance the activity of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the effect of the second active agent is not additive, but synergistic. In embodiments, the second activeAtty. Docket No.0282-0009WO2 agent is a chemotherapeutic agent (e.g., gemcitabine, decitabine, PEGylated liposomal doxorubicin (PLD), or nab-paclitaxel ) or a targeted therapy (e.g., bevacizumab) or a multi- modal therapy (e.g. a chemotherapeutic agent and a targeted therapy).

[0148] In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule and the second active agent are administered in a regimen, wherein the heterodimeric TCR- anti-CD3 antibody fusion molecule is administered as described herein, and the second active agent (i.e., combination partner) is as outlined in FIG.9. In some instances, the second active agent is administered prior to starting the treatment of the heterodimeric TCR-anti- CD3 antibody fusion molecule. In some embodiments, the administration of the second active agent is completed before the first doing of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the second active agent is administered prior to the start of the treatment the heterodimeric TCR-anti-CD3 antibody fusion molecule and then continues while the heterodimeric TCR-anti-CD3 antibody fusion molecule is also being administered. The second active agent and the heterodimeric TCR-anti-CD3 antibody fusion molecule can be administered concurrently, e.g., during the same regimens. In some embodiments, the second active agent follows a regimen as found in FIG.9 when being administered the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some the second active agent and the heterodimeric TCR-anti-CD3 antibody fusion molecule are administered on the same day (when the dosing regimen aligns that both active agents are administered on the same day). For example, the second active agent and the heterodimeric TCR-anti-CD3 antibody fusion molecule can be administered sequentially on the same day.

[0149] In some instances, administration of the second active agent starts at the same time as administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, administration of the second active agent ceases before starting the regimen of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, administration of the second active agent ceases at some time during the regimen of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, administration of the second active agent and administration of the heterodimeric TCR-anti- CD3 antibody fusion molecule cease at the same time.

[0150] In some embodiments, when the heterodimeric TCR-anti-CD3 antibody fusion molecule and the second active agent are administered on the same day, they are not administered at the same time, e.g., through the same IV line or given at the exact same time.Atty. Docket No.0282-0009WO2

[0151] In some embodiments, the second active agent comprises a chemotherapeutic agent, a check point inhibitor, a second, i.e., distinct, heterodimeric TCR-anti-CD3 antibody fusion molecule, a targeted therapeutic, hypomethylating agent, and / or multi-modal therapy. In some embodiments, the second active agent comprises a checkpoint inhibitor. In some embodiments, the second active agent comprises a checkpoint inhibitor. In some embodiments, the second active agent comprises a hypomethylating agent. In some embodiments, the second active agent comprises a second TCR-anti-CD3 antibody fusion molecule.

[0152] In some embodiments, the second active agent is a chemotherapeutic agent. In some embodiments, the second active agent is a biologic agent, e.g., a PD-1 inhibitor, a T-cell inactivator, a BRAF inhibitor, or a MEK inhibitor. In some embodiments, the second active agent comprises a checkpoint inhibitor. In some embodiments, the second active agent is a hypomethylating agent. In some embodiments, the chemotherapeutic agent is a hypomethylating agent. In some embodiments, the second active agent is a second TCR-anti- CD3 antibody fusion molecule.

[0153] In some embodiments, the second or more active agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent comprises gemcitabine, nab-paclitaxel, PEGylated liposomal doxorubicin (PLD), docetaxel, carboplatin, paclitaxel, doxorubicin, pemetrexed, or a combination thereof. In some embodiments, the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is PLD. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the chemotherapeutic agent is pemetrexed. In some embodiments, the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is carboplatin / paclitaxel. Gemcitabine is a nucleoside metabolic inhibitor indicated both as monotherapy and in combination therapy for multiple cancers. nab-paclitaxel is a second-generation semi-synthetic taxane conjugated to albumin that inhibits microtubule depolymerization, thereby leading to cell cycle arrest. PLD is an anthracycline topoisomerase inhibitor indicated, in combination, for use in the treatment of multiple cancers.

[0154] In some embodiments, the chemotherapeutic agent comprises gemcitabine or nab- paclitaxel. Any of the listed chemotherapeutic agents can be administered, e.g., in the amounts and regimens, as outlined in their respective Prescribing Information.Atty. Docket No.0282-0009WO2

[0155] In some embodiments, the chemotherapeutic agent is co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the chemotherapeutic agent is administered 1 to 12 week, 1 to 10 weeks, 1 to 8 weeks, or 1 to 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the chemotherapeutic agent is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the chemotherapeutic agent is administered 1 to 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the chemotherapeutic agent is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered after treatment with the chemotherapeutic agent is complete.

[0156] In some embodiments, the chemotherapeutic agent dose comprises about 10 to about 1000 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises about 10 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises less than about 10 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises greater than about 10 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises greater than about 1000 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises less than about 1000 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises about 1000 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises about 100 mg / m2. In some embodiments, the chemotherapeutic agent dose comprises AUC 1 to about AUC 10.

[0157] In some embodiments, the chemotherapeutic agent is administered once a week (QW) to once a month. In some embodiments, the chemotherapeutic agent is administered once every 2 weeks (Q2W). In some embodiments, the chemotherapeutic agent is administered once every 3 weeks (Q3W). In some embodiments, the chemotherapeutic agent is administered once every 4 weeks (Q4W). In some embodiments, the chemotherapeutic agent is administered once every 5 weeks (Q5W). In some embodiments, the chemotherapeutic agent is administered once every 6 weeks (Q6W). In some embodiments, the chemotherapeutic agent is administered once one week and off for three weeks; once a week for three weeks and off one week; once a week for two weeks and off two weeks; onceAtty. Docket No.0282-0009WO2 a week for two weeks and off one week; once every other week; once one week and off for two weeks; once one week and off for four weeks; once a week for two weeks and off for three weeks; once a week for three weeks and off for two weeks; once a week for four weeks and off for one week; once one week and off for five weeks; once a week for two weeks and off for four weeks; once a week for three weeks and off for three weeks; once a week for four weeks and off for two weeks; once a week for five weeks and off for a week.

[0158] In some embodiments, the chemotherapeutic agent is administered for at least 10 weeks. In some embodiments, the chemotherapeutic agent is administered for at least 40 weeks. In some embodiments, the chemotherapeutic agent is administered for the duration of the dosing regimen.

[0159] In some embodiments, the second active agent comprises: atezolizumab (Tecentriq®), avelumab (Bavencio®), bevacizumab (Avastin®), binimetinib (Mektovi®), encorafenib (Braftovi®), cobimetinib fumarate (Cotellic®), dabrafenib (e.g. dabrafenib mesylate (Tafinlar®)), dacarbazine, durvalumab (Imfinzi®), galunisertib, gemcitabine (Gemzar®), interferon, talimogene laherparepvec (Imlygic®), recombinant interferon alfa-2b (Intron® A), pembrolizumab (Keytruda®), tebentafusp-tebn (Kimmtrak®), trametinib dimethyl sulfoxide (Mekinist®), merestinib, nivolumab (Opdivo®), nivolumab and relatlimab-rmbw (Opdualag®), osimertinib (Tagrisso®), aldesleukin (Proleukin®), tremelimumab (Imjudo®), ipilimumab (Yervoy®), vemurafenib (Zelboraf®) or a combination thereof. In some embodiments, the second active agent is bevacizumab. Any of the listed second active agents can be administered as outlined in their Prescribing Information.

[0160] In some embodiments, the second active agent comprises: atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), bevacizumab (Avastin®), binimetinib, braftovi (Encorafenib), cobimetinib fumarate (Cotellic®), dabrafenib (for example, dabrafenib mesylate (Tafinlar®)), dacarbazine, durvalumab (IMFINZI®), encorafenib, galunisertib, gemcitabine, interferon, talimogene laherparepvec (Imlygic®), recombinant interferon alfa- 2b (Intron A), ipilimumab, pembrolizumab (Keytruda®), tebentafusp-tebn (Kimmtrak®), trametinib dimethyl sulfoxide (Mekinist®), binimetinib (Mektovi®), merestinib, nivolumab (Opdivo®), nivolumab and relatlimab-rmbw (Opdualag®), osimertinib, aldesleukin (Proleukin®), tremelimumab, vemurafenib, Ipilimumab (Yervoy®), vemurafenib (Zelboraf®) or a combination thereof. In some embodiments, the second active agentAtty. Docket No.0282-0009WO2 comprises osimertinib. In some embodiments, the checkpoint inhibitor comprises bevacizumab. Any of the listed second active agents (e.g., checkpoint inhibitors) can be administered as outlined in their Prescribing Information.

[0161] In some embodiments, the second active agent comprises a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor comprises: atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), pembrolizumab (Keytruda), , nivolumab (Opdivo®), nivolumab and relatlimab-rmbw (Opdualag®), tremelimumab (Imjudo®), ipilimumab (Yervoy®), or a combination thereof. In some embodiments, the checkpoint inhibitor comprises atezolizumab, avelumab, durvalumab ipilimumab, pembrolizumab, nivolumab or a combination thereof. In some embodiments, the checkpoint inhibitor comprises pembrolizumab. In some embodiments, the checkpoint inhibitor is bevacizumab. In some embodiments the checkpoint inhibitor is nivolumab. Any of the listed checkpoint inhibitors can be administered as outlined in their Prescribing Information.

[0162] In some embodiments, the checkpoint inhibitor is co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the checkpoint inhibitor is administered 1 to 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the checkpoint inhibitor is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the checkpoint inhibitor is administered 1 to 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the checkpoint inhibitor is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered after treatment with the checkpoint inhibitor is complete.

[0163] In some embodiments, the checkpoint inhibitor dose comprises about 10 mcg to about 500 mg. In some embodiments, the checkpoint inhibitor dose comprises about 10 mcg. In some embodiments, the checkpoint inhibitor dose comprises about 20 mcg. In some embodiments, the checkpoint inhibitor dose comprises about 30 mcg. In some embodiments, the checkpoint inhibitor dose comprises about 68 mcg. In some embodiments, the checkpoint inhibitor dose comprises about 500 mg. In some embodiments, the checkpoint inhibitor dose comprises about 400 mg. In some embodiments, the checkpoint inhibitor dose comprisesAtty. Docket No.0282-0009WO2 about 200 mg. In some embodiments, the checkpoint inhibitor dose comprises about 800 mg. In some embodiments, the checkpoint inhibitor dose comprises about 1 mg / kg to about 100 mg / kg. In some embodiments, the checkpoint inhibitor dose comprises about 1 mg / kg. In some embodiments, the checkpoint inhibitor dose comprises about 100 mg / kg. In some embodiments, the checkpoint inhibitor dose comprises about 15 mg / kg.

[0164] In some embodiments, the checkpoint inhibitor is administered once a week (QW) to once a month. In some embodiments, the checkpoint inhibitor is administered once every 2 weeks (Q2W). In some embodiments, the checkpoint inhibitor is administered once every 3 weeks (Q3W). In some embodiments, the checkpoint inhibitor is administered once every 4 weeks (Q4W). In some embodiments, the checkpoint inhibitor is administered once every 5 weeks (Q5W). In some embodiments, the checkpoint inhibitor is administered once every 6 weeks (Q6W). In some embodiments, the checkpoint inhibitor is administered once one week and off for three weeks; once a week for three weeks and off one week; once a week for two weeks and off two weeks; once a week for two weeks and off one week; once every other week; once one week and off for two weeks; once one week and off for four weeks; once a week for two weeks and off for three weeks; once a week for three weeks and off for two weeks; once a week for four weeks and off for one week; once one week and off for five weeks; once a week for two weeks and off for four weeks; once a week for three weeks and off for three weeks; once a week for four weeks and off for two weeks; once a week for five weeks and off for a week.

[0165] In some embodiments, the checkpoint inhibitor is administered for at least 10 weeks. In some embodiments, the checkpoint inhibitor is administered for at least 40 weeks. In some embodiments, the checkpoint inhibitor is administered for the duration of the dosing regimen.

[0166] In some embodiments, the second active agent comprises a hypomethylating agent. In some embodiments, the hypomethylating agent comprises: azacitidine, decitabine, cytidine, cedazuridine, guadecitabine, 5-fluro-2’-deoxycytidine, zebularine, CP-4200, RG108, nanaomycin A or any combination or modification thereof. In some embodiments, the hypomethylating agent comprises decitabine. Any of the listed hypomethylating agent can be administered as outlined in their Prescribing Information.

[0167] In some embodiments, the hypomethylating agent is co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments theAtty. Docket No.0282-0009WO2 hypomethylating agent is administered 1 to 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments the hypomethylating agent is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the hypomethylating agent is administered 1 to 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the hypomethylating agent is administered 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks or 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule. In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered after treatment with the hypomethylating agent is complete.

[0168] In some embodiments, the hypomethylating agent dose comprises about 0.01 mg / kg to about 1 mg / kg. In some embodiments, the hypomethylating agent dose comprises about 0.01 mg / kg. In some embodiments, the hypomethylating agent dose comprises about 0.07 mg / kg. In some embodiments, the hypomethylating agent dose comprises about 0.2 mg / kg. In some embodiments, the hypomethylating agent dose comprises about 0.6 mg / kg. In some embodiments, the hypomethylating agent dose comprises about 20 to 45 mg / m2 / day. In some embodiments, the hypomethylating agent dose comprises 75 to 90 % less than the 20 to 45 mg / m2 / day dose.

[0169] In some embodiments, the hypomethylating agent is administered once a week (QW) to once a month. In some embodiments, the hypomethylating agent is administered once every 2 weeks (Q2W). In some embodiments, the hypomethylating agent is administered once every 3 weeks (Q3W). In some embodiments, the hypomethylating agent is administered once every 4 weeks (Q4W). In some embodiments, the hypomethylating agent is administered once every 5 weeks (Q5W). In some embodiments, the hypomethylating agent is administered once every 6 weeks (Q6W). In some embodiments, the hypomethylating agent is administered once a week.

[0170] In some embodiments, the hypomethylating agent is administered for at least 10 weeks. In some embodiments, the hypomethylating agent is administered for at least 40 weeks. In some embodiments, the hypomethylating agent is administered for the duration of the dosing regimen.Atty. Docket No.0282-0009WO2

[0171] In some embodiments, the second active agent comprises a “targeted therapeutic.” In some embodiments, the targeted therapeutic is an antibody, e.g., a monoclonal antibody. In some embodiments, the targeted therapeutic comprises osimertinib, bevacizumab, dabrafenib, and trametinib, or combinations thereof, e.g., dabrafenib / trametinib. In some embodiments, the targeted therapeutic comprises osimertinib. In some embodiments, the targeted therapeutic comprises trametinib. In some embodiments, the targeted therapeutic recognizes VEGF, e.g., VEGF-A or ANGPT2. In some embodiments, the targeted therapeutic blocks pro-angiogenic pathways, either directly or indirectly. Any of the listed commercial targeted therapeutics can be administered as outlined in their Prescribing Information.

[0172] In some embodiments, the targeted therapeutic dose comprises about 0.01 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, or about 15 mg / kg of the targeted therapeutic, e.g., bevacizumab. In some embodiments, the targeted therapeutic dose comprises about 0.1 mg / day to about 500 mg / day, about 1 mg / day to about 250 mg / day, about 10 mg / day to about 200 mg / day, about 50 mg / day to about 150 mg / day, about 60 mg / day to about 100 mg / day, or about 80 mg / day of the targeted therapeutic, e.g., osimertinib. In some embodiments, the targeted therapeutic dose comprises about 50 mg / day to about 500 mg / day, about 150 mg / day to about 400 mg / day, about 200 mg / day to about 350 mg / day, about 550 mg / day to about 350 mg / day, or about 300 mg / day of the targeted therapeutic, e.g., dabrafenib.

[0173] In some embodiments, the targeted therapeutic is administered once a week (QW) to once a month. In some embodiments, the targeted therapeutic is administered once every 2 weeks (Q2W). In some embodiments, the targeted therapeutic is administered once every 3 weeks (Q3W). In some embodiments, the targeted therapeutic is administered once every 4 weeks (Q4W). In some embodiments, the targeted therapeutic is administered once every 5 weeks (Q5W). In some embodiments, the targeted therapeutic is administered once every 6 weeks (Q6W). In some embodiments, the targeted therapeutic is administered once a week. In some embodiments, the targeted therapeutic is administered daily. In some embodiments, the targeted therapeutic is administered twice daily.

[0174] In some embodiments, the second active agent comprises a second heterodimeric TCR-anti-CD3 antibody fusion molecule, e.g., tebentafusp. tebentafusp is a bispecific gp100Atty. Docket No.0282-0009WO2 peptide-HLA-directed CD3 T cell engager indicated for the treatment of HLA-A*02:01- positive adult patients with unresectable or metastatic uveal melanoma.

[0175] In some embodiments, the second heterodimeric TCR-anti-CD3 antibody fusion molecule is administered 10 - 40 mcg on Day 1, 20-50 mcg on Day 6-10, 50-75 mcg on Day 13-18, and 50-80 mcg once every week thereafter. In some embodiments, the second heterodimeric TCR-anti-CD3 antibody fusion molecule 20 mcg intravenously on Day 1, 30 mcg intravenously on Day 8, 68 mcg intravenously on Day 15, and 68 mcg intravenously once every week thereafter. Any commercial second heterodimeric TCR-anti-CD3 antibody fusion molecule can be administered as outlined in their Prescribing Information.

[0176] In some embodiments, the second active agent is pegylated liposomal doxorubicin (PLD). The PLD can be administered according to its Prescribing Information. In some embodiments, the PLD is administered at a dose intensity of about 10 mg / m2weekly, e.g., about 20 mg / m2biweekly, 30 mg / m2every three weeks, 40 mg / m2every 4 weeks, 50 mg / m2every 5 weeks or 60 mg / m2every 6 weeks. In some embodiments, the subject is administered about 40 mg / m2to 60 mg / m2every 4 weeks to every 6 weeks, or about 40 mg / m2every 4 weeks.

[0177] In some embodiments, the second active agent comprises a multimodal therapy, e.g., combinations of second active agents as described herein. In some embodiments, the multimodal therapy can include a biologic and a chemotherapeutic agent as describe herein. For example, in some embodiments, the multimodal therapy can include: a chemotherapeutic and a checkpoint inhibitor, a chemotherapeutic and a targeted therapy, a chemotherapeutic and a hypomethylating agent, a checkpoint inhibitor and a targeted therapy, a checkpoint inhibitor and a hypomethylating agent, or a targeted therapy and a hypomethylating agent. In some embodiments the multi-modal therapy comprises a targeted therapy and a chemotherapeutic agent. In some embodiments, the multi-modal therapy comprises bevacizumab and a chemotherapeutic agent. In some embodiments, the multi-modal therapy comprises pembrolizumab and a chemotherapeutic agent.

[0178] In some embodiments, the second active agent can comprise two, three or four chemotherapeutics, two, three or four checkpoint inhibitors, two, three or four targeted therapies, or two three or four hypomethylating agents.Atty. Docket No.0282-0009WO2

[0179] In some embodiments, the second active agent can comprise carboplatin and paclitaxel. In some embodiments, the second active agent can comprise pembrolizumab and paclitaxel. In some embodiments, the second active agent can comprise pembrolizumab, paclitaxel, and carboplatin. In some embodiments, the second active agent can comprise pembrolizumab, pemetrex and carboplatin. In some embodiments, the second active agent can comprise bevacizumab, gemcitabine, PLD, and carboplatin.

[0180] In some embodiments, the second active agent is co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule, i.e., is administered on the same days as the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0181] In some embodiments, a second or more active agent is administered according to a dosing amount and regimen known for that specific active agent. In some embodiments, the second or more active agent is administered once a week to once a month. In some embodiments, the second or more active agent is administered once a week. In some embodiments, the second or more active agent can be administered at a reduced frequency or reduced dosage amounts when co-administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0182] In some embodiments, the second or more active or more agent is administered for the duration of the dosing regimen. In some embodiments, the second or more active agent is administered for a period of time known for that specific active agent(s). In some embodiments, the second or more active agent is administered for at least 10 weeks. In some embodiments, the second or more active agent is administered for at least 20 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, at least 60 weeks, at least 70 weeks, at least 80 weeks, or at least 90 weeks. In some embodiments, the second or more active agent is administered for at least 40 weeks. In some embodiments, the second or more active agent is administered for a shorter duration when co-administered with the heterodimeric TCR-anti- CD3 antibody fusion molecule relative to the second or more active agent(s) being administered as a monotherapy.

[0183] In a specific embodiment to treatment with heterodimeric TCR-anti-CD3 antibody fusion molecule and a second or more active agent, the disclosure provides a method of treating a non-small or non-small cell lung cancer or ovarian carcinoma in a subject comprising administering to the subject:Atty. Docket No.0282-0009WO2

[0184] (I) a composition comprising a heterodimeric TCR-anti-CD3 antibody fusion molecule, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, and (II) a second active agent, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose; and (B) a second active agent, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel, and wherein the second active agent is administered once every week to once every month.

[0185] Administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule and or the second active agent can be by any conventional means known for administering anti- cancer biologics, e.g., intravenous (e.g., intravenous cannula (IVC) or central venous access device (CVAD)), intramuscular, subcutaneous, orally, subcutaneously, sublingually, intramuscularly, intravenously, intranasally, transdermally, or any combination thereof. In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule and / or second active agent can be administered by intravenous infusion. In some embodiments, theAtty. Docket No.0282-0009WO2 heterodimeric TCR-anti-CD3 antibody fusion molecule and / or second active agent can be administered orally.

[0186] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (II) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, decitabine, PLD, pembrolizumab, tebentafusp or nab- paclitaxel in a dosing regimen.

[0187] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, decitabine, PLD, or nab-paclitaxel in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 3 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 10 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, andAtty. Docket No.0282-0009WO2 (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks.

[0188] In another specific embodiments, the disclosure provides a method of treating non- small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, wherein the second active agent is a chemotherapeutic agent, e.g., gemcitabine, decitabine, PLD, or nab-paclitaxel, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 20 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 160 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and then every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks.

[0189] In some embodiments, the methods provided herein can be directed to a PRAME- positive cancer, e.g., cancers including, but not limited to, melanoma, lung cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, bladder cancer, head and neck cancer, uterine cancer, Acute myeloid leukemia, chronic myeloid leukemia, and Hodgkin’sAtty. Docket No.0282-0009WO2 lymphoma. In some embodiments, the disclosure provides a method of treating a PRAME- positive cancer in a subject comprising administering to the subject a composition comprising a heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the heterodimeric TCR-anti- CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the heterodimeric TCR-anti-CD3 antibody fusion molecule than the second dose,

[0190] In some embodiments, the PRAME-positive cancer is a non-small or small cell lung cancer. In some embodiments, the PRAME-positive cancer is an ovarian carcinoma.

[0191] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, PLD, nab-paclitaxel, pembrolizumab, tebentafusp,Atty. Docket No.0282-0009WO2 osimertinib, docetaxel, bevacizumab, carboplatin, paclitaxel, dabrafenib, trametinib, pemetrexed, or decitabine, in a dosing regimen as outlined herein.

[0192] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, PLD, nab-paclitaxel, pembrolizumab, tebentafusp.

[0193] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising osimertinib, docetaxel, or carboplatin.

[0194] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising one of the following combinations: carboplatin+paclitaxel, bevcizumab+gemcitabine+carboplatin, or pembrolizumab+ paclitaxel+carboplatin.

[0195] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, (II) a second composition comprising a second active agent, wherein the second active agent is carboplatin, and (III) a third composition comprising a third active agent, wherein the third active agent comprises Paclitaxel in a dosing regimen.

[0196] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, and (III) a third composition comprising a third active agent, wherein the third active agent comprises osimertinib in a dosing regimen.Atty. Docket No.0282-0009WO2

[0197] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, (III) a third composition comprising a third active agent, wherein the third active agent comprises bevacizumab, (IV) a fourth composition comprising a fourth active agent, wherein the fourth active agent comprises carboplatin, and (V) a fifth composition comprising a fifth active agent, wherein the fifth active agent comprises paclitaxel in a dosing regimen.

[0198] In specific embodiments, the disclosure provides a method of treating a non-small or small cell lung cancer, or ovarian carcinoma, in a subject comprising administering to the subject a composition comprising a (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, (II) a second composition comprising a second active agent, wherein the second active agent is gemcitabine, (III) a third composition comprising a third active agent, wherein the third active agent comprises carboplatin, and (IV) a fourth composition comprising a fourth active agent, wherein the fourth active agent comprises paclitaxel in a dosing regimen.

[0199] In other specific embodiments, the disclosure provides a method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a chemotherapeutic agent (and such chemotherapeutic agent can be gemcitabine, PLD, carboplatin / paclitaxel, or any combination thereof). In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is PLD. In some embodiments, the chemotherapeutic agent is carboplatin / paclitaxel.

[0200] In other specific embodiments, the disclosure provides a method of treating ovarian carcinoma comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C) and (II) a second composition comprising a second active agent where such agent is a targeted therapy (and such targeted therapy can be bevacizumab).Atty. Docket No.0282-0009WO2

[0201] In other specific embodiments, the disclosure provides a method of treating ovarian carcinoma comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C) and (II) a second composition comprising a second active agent where such agent is a multimodal therapy (and such multi-modal therapy can be carboplatin / paclitaxel / pembrolizumab or carboplatin / gemcitabine / bevacizumab). In some embodiments, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some embodiments, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0202] In other specific embodiments, the disclosure provides a method of treating platinum-sensitive ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a chemotherapeutic agent (and such chemotherapeutic agent can be gemcitabine, PLD, carboplatin / paclitaxel, or any combination thereof). In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is PLD. In some embodiments, the chemotherapeutic agent is carboplatin / paclitaxel.

[0203] In other specific embodiments, the disclosure provides a method of treating platinum-sensitive ovarian carcinoma comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC- F106C) and (II) a second composition comprising a second active agent where such agent is a targeted therapy (and such targeted therapy can be bevacizumab).

[0204] In other specific embodiments, the disclosure provides a method of treating platinum-sensitive ovarian carcinoma comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC- F106C) and (II) a second composition comprising a second active agent where such agent is a multimodal therapy (and such multi-modal therapy can be carboplatin / paclitaxel / pembrolizumab or carboplatin / gemcitabine / bevacizumab). In someAtty. Docket No.0282-0009WO2 embodiments, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some embodiments, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0205] In other specific embodiments, the disclosure provides a method of treating platinum-resistant ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a chemotherapeutic agent (and such chemotherapeutic agent can be gemcitabine, PLD, carboplatin / paclitaxel, or any combination thereof). In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is PLD. In some embodiments, the chemotherapeutic agent is carboplatin / paclitaxel.

[0206] In other specific embodiments, the disclosure provides a method of treating platinum-resistant ovarian carcinoma administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C) and (II) a second composition comprising a second active agent where such agent is a targeted therapy (and such targeted therapy can be bevacizumab).

[0207] In other specific embodiments, the disclosure provides a method of treating platinum-resistant ovarian carcinoma comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC- F106C) and (II) a second composition comprising a second active agent where such agent is a multimodal therapy (and such multi-modal therapy can be carboplatin / paclitaxel / pembrolizumab or carboplatin / gemcitabine / bevacizumab). In some embodiments, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some embodiments, the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

[0208] In other specific embodiments, the disclosure provides a method of treating lung cancer (preferably NSCLC) comprising administering to the subject a composition comprising: (I) a heterodimeric TCR anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC- F106C), and (II) a second composition comprising a second active agent where such agent isAtty. Docket No.0282-0009WO2 a chemotherapeutic agent (gemcitabine, docetaxel, or a combination thereof). In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is docetaxel.

[0209] In other specific embodiments, the disclosure provides a method for treating non- small cell lung cancer comprising administering to the subject a composition comprising: (I) a heterodimeric TCR anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a targeted therapy (e.g., Osimertinib).

[0210] In other specific embodiments, the disclosure provides a method for treating non- small cell lung cancer comprising administering to the subject a composition comprising: (I) a heterodimeric TCR anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a multi- modal therapy (and such multi-modal therapy can be carboplatin / paclitaxel / pembrolizumab or carboplatin / pemetrexed / pembrolizumab) In some embodiments, the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab. In some embodiments, the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

[0211] In other specific embodiments, the disclosure provides a method of treating melanoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a second heterodimeric TCR-anti-CD3 antibody fusion molecule (such as tebentafusp).

[0212] In other specific embodiments, the disclosure provides a method of treating melanoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a targeted therapy (such as dabrafenib / trametinib).Atty. Docket No.0282-0009WO2

[0213] In other specific embodiments, the disclosure provides a method of treating other cancers in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a hypomethylating agent (such as decitabine, preferably low-dose decitabine).

[0214] In other specific embodiments, the disclosure provides a method of treating other cancers in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule (where such molecule can correspond to one targeting PRAME, preferably where such molecule is IMC-F106C), and (II) a second composition comprising a second active agent where such agent is a chemotherapeutic agent (such as PLD or carboplatin / paclitaxel). In some embodiments, the chemotherapeutic agent is PLD. In some embodiments, the chemotherapeutic agent is carboplatin / paclitaxel. Composition / kit

[0215] For administration to subjects, the heterodimeric TCR-anti-CD3 antibody fusion molecule and / or second or more active agent of the disclosure, can be provided as part of a composition together with one or more pharmaceutically acceptable carriers or excipients. This pharmaceutical composition can be in any suitable form, (e.g., depending upon the desired method of administering it to a subject). It can be provided in unit dosage form and will generally be provided in a sealed container and can be provided as part of a kit. Such a kit would normally (although not necessarily) include instructions for use, and specifically can include detailed instructions related to the dosage amounts and the timing of administration. The kit can include a plurality of containers.

[0216] In some embodiments, the kit can comprise more than one container, wherein each container comprises a specific amount of lyophilized heterodimeric TCR-anti-CD3 antibody fusion molecule. The lyophilized heterodimeric TCR-anti-CD3 antibody fusion molecule in one container can be reconstituted in a liquid vehicle, e.g., a buffered saline solution, prior to administration to the subject, while the remaining containers remain lyophilized. In some embodiments, the kit can comprise more than one container, wherein each container comprises a specific amount of heterodimeric TCR-anti-CD3 antibody fusion molecule,Atty. Docket No.0282-0009WO2 wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule is solubilized in a liquid vehicle, e.g., a buffer system and / or one or more excipients.

[0217] Thus, for example, the kit can comprise (i) one to five first containers, each first container comprising a first dose comprising 2 to 4 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one to five second containers, each second container comprising a second dose comprising 5 to 14 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, and (iii) three or more maintenance containers, each maintenance container comprising a maintenance dose comprising 15 to 55 µg of the heterodimeric TCR- anti-CD3 antibody fusion molecule, and (iv) one or more containers comprising a second active agent dose of 10-1000 mg / m2; (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen. In some embodiments, the instructions specify a dosing regimen comprising (a) administering the first dose weekly, (b) administering the second dose weekly, (c) administering the maintenance dose weekly during the first phase, (d) administering the maintenance dose every 2 weeks during the second phase, and (e) administering the maintenance dose every 4 weeks during the third phase, and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0218] In some embodiments, the disclosure provides a kit comprising: (i) one first container comprising a first dose comprising 2 to 4 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 5 to 14 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 15 to 55 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose of 10-1000 mg / m2; (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, wherein the dosing regimen is specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering aAtty. Docket No.0282-0009WO2 maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, and (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0219] In some embodiments, the disclosure provides a kit comprising: (i) one first container comprising a first dose comprising 20 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 40 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 160 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose of 10-1000 mg / m2; (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, wherein the dosing regimen is specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering a maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, and (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0220] In some embodiments, the heterodimeric TCR-anti-CD3 antibody fusion molecule in any of the kits described herein comprise (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprisesAtty. Docket No.0282-0009WO2 complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

[0221] In some embodiments, the disclosure provides a kit for the ascending dose regimen, the kit comprising: (i) one first container comprising a first dose comprising 3 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 10µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) three or more maintenance containers, each maintenance container comprising a maintenance dose comprising 4 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0222] In some embodiments, the disclosure provides a kit for the ascending dose regimen, the kit comprising: (i) one first container comprising a first dose comprising 20 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 40 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) three or more maintenance containers, each maintenance container comprising a maintenance dose comprising 160 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule.

[0223] In some embodiments, the disclosure provides a kit for the maintenance dose regimen, the kit comprising: three or more maintenance containers, each maintenance container comprising a maintenance dose comprising 40 µg of the heterodimeric TCR-anti- CD3 antibody fusion molecule. In some embodiments, the kit for the maintenance dose regimen comprises enough maintenance containers for one month,2 months, three months, 4 months, 5 months, or 6 months.

[0224] In some embodiments, the disclosure provides a kit for the maintenance dose regimen, the kit comprising: three or more maintenance containers, each maintenanceAtty. Docket No.0282-0009WO2 container comprising a maintenance dose comprising 160 µg of the heterodimeric TCR-anti- CD3 antibody fusion molecule.

[0225] In some embodiments, the kit for the maintenance dose regimen comprises enough maintenance containers for one month, 2 months, three months, 4 months, 5 months, or 6 months.

[0226] The disclosure provides that the kit can comprise 1 or 2 first containers, 1 or 2 second containers, and various numbers of maintenance containers. For example, in some embodiments, the kit comprises 2 to 60 maintenance containers, 3 to 50 maintenance containers, 4 to 40 maintenance containers, 4 to 30 maintenance containers, 4 to 20 maintenance containers, 4 to 16 maintenance containers, 4 to 12 maintenance containers, or 4 to 8 maintenance containers. For example, in some embodiments, the kit comprises 2 to 10 maintenance containers,

[0227] In some embodiments, the first dose, the second dose and / or the maintenance dose further comprise(s) a pharmaceutically acceptable excipient to form a first pharmaceutical formulation, second pharmaceutical formulation, and / or maintenance pharmaceutical formulation, respectively. In some embodiments, the pH of the first, second and / or maintenance pharmaceutical formulation is pH adjusted. In some embodiments, the first, second and / or maintenance pharmaceutical formulation has a pH of about 6.5 to about 7.5.

[0228] In some embodiments, the kit comprises only one anti-cancer therapeutic agent. In some embodiments, the kit comprises the heterodimeric TCR-anti-CD3 antibody fusion molecule and further comprises a second, third, fourth, and / or fifth therapeutic agent. In some embodiments, the second, third, fourth, and / or fifth therapeutic agent in the kit comprises a checkpoint inhibitor, a chemotherapeutic agent, another TCR-anti-CD3 antibody fusion molecule, and / or a hypomethylating agent. In some embodiments, the second, third, fourth, and / or fifth therapeutic agent in the kit comprises gemcitabine, nab-paclitaxel, PEGylated liposomal doxorubicin (PLD), docetaxel, carboplatin, paclitaxel, doxorubicin, pemetrexed, aldesleukin, atezolizumab (TECENTRIQ®), avelumab, bevacizumab (Avastin®), binimetinib, Braftovi (encorafenib), cobimetinib fumarate, Cotellic (cobimetinib fumarate), dabrafenib mesylate, dacarbazine, durvalumab. encorafenib, galunisertib, gemcitabine, IL-2 (aldesleukin), interferon, Imlygic (talimogene laherparepvec), Intron A (recombinant interferon alfa-2b), ipilimumab, Keytruda (pembrolizumab), KIMMTRAK (tebentafusp),Atty. Docket No.0282-0009WO2 Mekinist (trametinib dimethyl sulfoxide), Mektovi (binimetinib), merestinib, nivolumab, nivolumab and relatlimab-rmbw, Opdivo (nivolumab), Opdualag (nivolumab and relatlimab- rmbw), Tagrisso (osimertinib), Proleukin (aldesleukin Tafinlar (dabrafenib mesylate), tebentafusp, trametinib dimethyl sulfoxide, tremelimumab, vemurafenib, Yervoy (ipilimumab), Zelboraf (vemurafenib), azacitidine, decitabine, cytidine, cedazuridine, guadecitabine, 5-fluro-2’-deoxycytidine, zebularine, CP-4200, RG108, nanaomycin A or any combination or modification thereof. In some embodiments, the second, third, fourth, and / or fifth therapeutic agent in the kit comprises a chemotherapeutic agent, e.g., gemcitabine, nab- paclitaxel, decitabine, tebentafusp or a combination thereof.

[0229] The kits described herein contain one or more containers, e.g., a first container comprising a first dose, a second container comprising a second dose, and / or a maintenance container comprising a maintenance dose. Suitable containers include, for example, bottles, vials, syringes, etc. The containers can be formed from a variety of materials such as glass or plastic. The container holds or contains a composition that comprises the heterodimeric TCR- anti-CD3 antibody fusion molecule the disclosure and can have a sterile access port (for example, the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The instructions, e.g., label or package insert ,indicates that the heterodimeric TCR-anti-CD3 antibody fusion molecule is used for treating a subject eligible for treatment, e.g., one having or predisposed to developing a disease described herein, with specific guidance regarding dosing amounts and intervals of the composition and any other medicament being provided. In some embodiments, the kit can further comprise an additional container comprising a pharmaceutically acceptable diluent buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and / or dextrose solution. The kit can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0230] Various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. Preferred features of each aspect of the disclosure are as for each of the other aspects mutatis mutandis. The documents referred to herein are incorporated by reference to the fullest extent permitted by law.Atty. Docket No.0282-0009WO2 EXAMPLES

[0231] The present disclosure has been described with respect to representative examples that are to be considered illustrative embodiments that do not limit the scope of the disclosure which is defined solely by the claims. All references to publications, including scientific publications, treatises, textbooks, patent applications and issued patents are hereby incorporated by reference for all purposes.

[0232] The trial design of this invention is complex and modular (see below). The initial trial design was focused on dose safety and tolerability, and determination of a maximum tolerated dose (MTD) and a recommended Phase 2 dose (RP2D). During the course of conducting the initial phase of the trial, and as a result of analyzing study data, the team determined that certain treatment approaches and regimens were beneficial, in particular combination treatment of IMC-F106C with certain chemotherapies in lung and ovarian cancer. From overall study analyses, the team also developed new hypotheses and then established a novel set of therapeutic approaches (as set forth below, including combination therapies with additional chemotherapies, targeted therapies, and hypomethylating agents). Example 1: IMC-F106C Clinical Trial

[0233] Patients have been treated in an ongoing Phase 1 / 2 clinical trial study of IMC- F106C (IMC-F106C-101) entitled “A Phase 1 / 2 First-in-Human Study of the Safety and Efficacy of IMC-F106C as a Single Agent and in Combination with Checkpoint Inhibitors in HLA A*02:01 Positive Participants with Advanced PRAME Positive Cancers.” The study was designed to assess the safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics, and antitumor activity of IMC-F106C when administered as monotherapy, and in combination with other therapies.

[0234] In the IMC-F106C-101 study, participants with advanced cancers include those with unresectable or metastatic melanoma, ovarian carcinoma, uterine carcinoma, NSCLC, and other PRAME-positive tumors that are relapsed from, refractory to, or intolerant of standard treatment regimens. The study is also evaluating combinations with different standard-of-care therapies, in participants with advanced cancers who are eligible for these standard therapies.

[0235] Despite the development and approval of new therapies, including targeted small- molecule therapeutics and immunotherapeutics, many patients will be refractory to or relapseAtty. Docket No.0282-0009WO2 following available treatment options. The unmet therapeutic need for these patients remains high and access to novel targeted therapies, such as IMC-F106C, have the potential to provide clinical benefit.

[0236] The trial design is complex, with the schema involving different modules depending on tumor type, akin to a complex basket trial. The high-level study schema can be seen in FIG.1.

[0237] IMC-F106C was administered using a step-dose regimen, amongst other reasons, to mitigate tumor lysis (FIG.2 and 3). Example 2: IMC-F106C Combination Treatments

[0238] In addition to monotherapy treatment, IMC-F106C has been evaluated in combination with standard therapies including a checkpoint inhibitor, chemotherapeutic agent, or another ImmTAC molecule.

[0239] Descriptions of particular therapeutic agents for use in combination treatment with IMC-F106C are described further below.

[0240] Checkpoint Inhibitors

[0241] PD-1 may be expressed on tumor-infiltrating lymphocytes and can contribute to the inhibition of the antitumor immune response. Binding of PD-1 to PD-L1, which may be expressed on tumor cells and antigen-presenting cells, results in inhibition of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Several monoclonal antibody therapeutics targeting PD-1 or PD-L1 (PD-[L]1), including atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab, have been approved for the treatment of various malignancies.

[0242] T-cell activation, including ImmTAC-mediated activation, induces PD-1 expression on T cells. Increased PD-L1 expression has been observed in tumors following ImmTAC treatment (Middleton et al.2020). This induction of both ligand and receptor may impair the T-cell response. In vitro studies have shown that checkpoint inhibitors can increase ImmTAC-redirected killing of PD-L1-positive cancer cells by PD-1-positive tumor- infiltrating T-cells (Petrovic et al.2021). Checkpoint inhibitors including pembrolizumab may enhance the initial activity of IMC-F106C and prevent T-cell exhaustion, therebyAtty. Docket No.0282-0009WO2 sustaining the effectiveness of the emerging antitumor immune response. In parallel, IMC- F106C-mediated redirection of effector T cells into tumors may help to overcome resistance to monotherapy checkpoint inhibitors resulting from poor T cell infiltration.

[0243] Pembrolizumab was administered according to the manufacturer’s prescribing information. Chemotherapy

[0244] Analyses of combination data as a whole as well as analyses of translational data revealed that efficacy of IMC-F106C is potentially linked to a participant’s immune fitness. From the study data, it emerged that chemotherapy treatment has the potential to reset immune fitness. Thus, combination approaches with additional chemotherapies were incorporated into the clinical trial design.

[0245] Gemcitabine, nab-paclitaxel, and PLD were selected as chemotherapeutic agent combination partners for IMC-F106C based on the fact that they are commonly used in multiple indications where PRAME expression is very prevalent, are relatively well-tolerated, and are non-lymphodepleting. Gemcitabine is a nucleoside metabolic inhibitor indicated both as monotherapy and in combination therapy for multiple cancers. Nab-paclitaxel is a second- generation semi-synthetic taxane conjugated to albumin that inhibits microtubule depolymerization, thereby leading to cell cycle arrest. PLD is an anthracycline topoisomerase inhibitor indicated, in combination, for use in the treatment of multiple cancers. In addition to direct anti-tumor activity, chemotherapy may augment immunotherapy by causing immunogenic cell death and disrupting tumor immune evasion.

[0246] Additional chemotherapy regimens have been incorporated into the study design, namely, docetaxel, carboplatin / paclitaxel (alone and in combination with bevacizumab or pembrolizumab) and carboplatin / pemetrexed (in combination with pembrolizumab. These regimens provide for treatment in early-line NSCLC, ovarian cancer, and / or uterine cancer.

[0247] Immunogenic cell death involves the release of potentially immunogenic tumor cell proteins and DAMPs. As an example, gemcitabine treatment of cancer cells induces classical DAMPs, cell-surface calreticulin, and soluble HSP70 and HMGP (Hayashi et al.2020). Chemotherapies including docetaxel, carboplatin, pemetrexed, paclitaxel and doxorubicin can also induce immunogenic cell death (Lau 2020, Schaer 2019, Flieswasser 2020). TheseAtty. Docket No.0282-0009WO2 signals can induce maturation and activation of dendritic cells, resulting in an increase in immunogenic antigen presentation. Because ImmTAC treatment increases the number of tumor-infiltrating T cells, the combination of ImmTAC treatment and chemotherapy may increase the likelihood of priming of T cells specific for newly shed tumor antigens.

[0248] The selected chemotherapies may also reduce immunosuppression mediated by myeloid cells including macrophages and MDSCs. Gemcitabine treatment can deplete intratumoral MDSCs (Eriksson et al.2016; Le et al.2009; Suzuki et al.2005), while paclitaxel can kill MDSCs and (at sub-cytotoxic concentrations) induce maturation into dendritic cells (Michels et al.2012). In vitro, ImmTAC-redirected tumor cell killing is sensitive to inhibition by M2-macrophages (alternatively activated, immunosuppressive), and in clinical studies of Tebentafusp in uveal melanoma there was an association between a high ratio of CD163-positive macrophages to T cells and poor clinical response (Hassel et al. 2021). Paclitaxel, PLD, and docetaxel have been shown to promote conversion of macrophages from an M2 to an M1 (classically activated, pro-inflammatory) phenotype (Takayama et al.2020; Wanderley et al.2018; Yamaguchi et al.2017). Agents that convert macrophages within the tumor microenvironment from an M2 to an M1 phenotype may promote anti-tumor activity and synergize with immunotherapies (Li, C. et al.2021).

[0249] Preclinical evaluation of the ImmTAC-chemotherapy combination showed enhanced tumor cell lysis when paclitaxel was administered either in combination with ImmTAC or sequentially administered (Bravo-Lopes et al.2019). Enhanced killing of tumor cells occurred despite paclitaxel impairing T cell proliferation. Prior exposure of either tumor cells or T cells to paclitaxel enhanced ImmTAC-mediated tumor cell killing with no effect on T cell proliferation.

[0250] Gemcitabine, nab-paclitaxel, PLD, docetaxel, pemetrexed, carboplatin, and paclitaxel were administered according to the manufacturer’s prescribing information.

[0251] The combination IMC-F106C / chemotherapy treatments demonstrated clinical activity. FIG.4A and FIG.4B show clinical activity with the combination treatment of nab- paclitaxel and IMC-F106C. FIG.4A is a graphical representation of the change in tumor size from baseline of patients where each bar represents an individual patient. As can be seen in FIG.4A, participants with non-small cell lung cancer (NSCLC), ovarian cancer (OC), breast cancer, and mucosal melanoma showed a reduction in tumor size, with the greatest reductionAtty. Docket No.0282-0009WO2 of tumor size to date observed in NSCLC and OC patients. FIG.4B is a different representation (spider plot) of the response in these patients, where the change in tumor size relative to baseline is shown over time and where each line represents an individual patient.

[0252] FIG.4C and FIG.4D show clinical activity with the combination treatment of gemcitabine and IMC-F106C. FIG.4C is a graphical representation of the change in tumor size from baseline of patients where each bar represents an individual patient. As can be seen in FIG.4C, participants with NSCLC and OC again showed the greatest reduction of tumor size to date. FIG.4D is a spider plot of the response in these patients, where the change in tumor size relative to baseline is shown over time and where each line represents an individual patient.

[0253] The data presented in FIGS.4A-D demonstrate that combination treatment with IMC-F106C and either nab-paclitaxel or gemcitabine results in clinical activity with the greatest response to date seen in NSCLC and OC patients. Each of these patients have had several prior lines of treatment with either no activity or regression. Thus, the combination treatments provide a critical option for treating cancer, particularly in patients who may not be responding well to standard-of-care therapies. Other ImmTAC Molecules

[0254] Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

[0255] Malignant melanoma arises from melanocytes in any organ and is characterized by the expression of gp100, the target protein of tebentafusp. Tebentafusp is designed to redirect T cells to kill gp100+ tumor cells. In a randomized Phase 3 study in metastatic uveal melanoma (IMCgp100-202), tebentafusp monotherapy demonstrated an OS benefit (HR of 0.51) compared with investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine (Nathan et al.2021). Tebentafusp has demonstrated promising OS as monotherapy in anti- PD-1-naïve metastatic non-uveal melanoma and in combination with anti-PD-L1 in previously pretreated metastatic non-uveal melanoma (Hamid et al.2021; Middleton et al. 2020).Atty. Docket No.0282-0009WO2

[0256] Expression and presentation of tumor antigens such as PRAME can show intra- tumoral heterogeneity. Cells presenting a reduced level of target pHLA may be less susceptible to killing by ImmTAC-redirected T cells, providing a possible resistance mechanism. A combination of 2 ImmTAC molecules would simultaneously target 2 tumor antigens (e.g., PRAME and gp100), which may render a larger population of tumor cells susceptible to killing. Additionally, in vitro data demonstrate increased cell killing when higher levels of target pHLA are present, specific to a single ImmTAC molecule. Thus, a combination therapy with 2 ImmTAC molecules may result in more ImmTAC molecules bound to a single tumor cell expressing the relevant pHLA complexes. A combination ImmTAC approach, therefore, may potentially lead to increased tumor cell killing relative to a single ImmTAC.

[0257] Tebentafusp, also known as KIMMTRAK, was administered in accordance with its prescribing information. Targeted Therapies

[0258] Leveraging IMC-F106C’s unique mechanism, certain targeted therapies were built into the trial design to provide opportunities to overlay IMF-F106C’s mechanism of action as part of underlying therapy, particularly with relapsed patients or for patients where benefit from prior treatment was flattening over time and / or trending towards disease progression.

[0259] Combinations with selected targeted therapies (osimertinib, bevacizumab, and dabrafenib / trametinib) were included. An overactive metabolism and inadequate blood supply contribute to the development of a hypoxic and acidic TME. In response to this hypoxia, certain pro-angiogenic cytokines like VEGF and ANGPT2 become more active, stimulating angiogenesis. The resulting disorganized angiogenesis further encourages the emergence of an immunosuppressive TME. By inhibiting VEGF, bevacizumab intervenes by blocking these pro-angiogenic pathways. This intervention leads to the normalization of blood vessels, thereby improving the blood flow and oxygen levels within the tumor environment. Consequently, the hypoxic TME is reversed, and the delivery of drugs to the tumor is enhanced. Inhibition of angiogenesis also remodels the TME by facilitating the infiltration of T cells and the maturation of DCs. It promotes the transformation of macrophages into a phenotype resembling M1-type macrophages, while reducing the proportions of Tregs and MDSCs (Yi et al.2022).Atty. Docket No.0282-0009WO2

[0260] Osimertinib, a third-generation EGFR kinase inhibitor, has demonstrated the ability to trigger DAMPs (Furukawa et al.2021). Dabrafenib and trametinib are BRAF and MEK inhibitors, respectively. Targeted inhibition of both EGFR and MEK, integral components of the MAPK pathway, has been observed to elevate the expression of MHC Class I molecules in laboratory settings. When TCR directed therapy against PRAME was combined with a MAPK pathway inhibitor, it resulted in heightened cell killing efficacy (Brea et al.2016).

[0261] Bevacizumab, osimertinib, dabrafenib, and trametinib were administered in accordance with its prescribing information. Hypomethylating Agents

[0262] As an additional innovative approach, the use of hypomethylating agents, which may promote PRAME expression, the target of IMC-F106C, was incorporated into the clinical trial design as part of a combination treatment approach.

[0263] Combination with low-dose decitabine, a hypomethylating agent (HMA) is combined with IMC-F106C. Currently HMAs are approved in hematologic malignancies (myelodysplastic syndrome and acute myeloid leukemia). Low-dose decitabine is used in order to improve immune function and increase tumor PRAME expression.

[0264] To date, several clinical studies have been completed evaluating HMAs as single agent therapy or in combination with other systemic therapy for safety and efficacy in solid tumors (George et al.2010; Samlowski et al.2005; Torres et al.2021; Taylor et al.2020; Jang et al.2023; Palomba et al.2022; Short et al.2022).

[0265] Non-cytotoxic (low) doses of decitabine have been shown to deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1) (Hoff et al.2018; Matei et al.2018; Fu et al. 2014; Garrido- Laguna et al.2013; Awada et al.2020; Bauman et al.2012; Ben-Baruch et al. 1993).

[0266] T cells within the TME are antigen-exposed, and persistent antigen stimulation causes CD8+ T cells to become functionally exhausted, with inhibitory receptors, perturbed proliferation and cytokine secretion, impaired immune memory, and altered metabolism (Wherry and Kurachi 2015). Targeting PRAME has been shown to be effective in patients with advanced cancers. The ability of PRAME-redirected T cells to recognize PRAME-Atty. Docket No.0282-0009WO2 positive tumor cells is based on the intensity of expression and co-expression of MHC class I. To evade immune surveillance, cancers evolve to suppress expression of IFNγ pathway genes, proteins involved in antigen presentation including MHC class I or beta-2 microglobulin (B2M), and cancer testes antigens via mutations or epigenetic silencing. Data suggest that epigenetic modulation may improve immune function through upregulation of expression of tumor-associated antigens (such as PRAME) and / or epigenetic reprogramming of T cell intrinsic programs and suppression of terminal differentiation (Pauken et al.2016; Li, X. et al.2023; Sen et al.2016).

[0267] HMAs may induce PRAME gene expression in a variety of cancer types (Wong et al., 2021; Yao et al.2013). This can result in immunomodulatory effects promoting higher anti-cancer activity, especially in tumors with lower PRAME expression (Chou et al.2012). Depletion of DNMT1 by non-cytotoxic doses of HMA in combination with the PRAME- directed ImmTAC molecule IMC-F106C may have improved anticancer activity.

[0268] When lung and ovarian cancer cell lines were pre-treated with a clinically relevant concentration of decitabine before being used as target cells in an ImmTAC-dependent T cell activation assay, increased T cell activation (as measured by interferon gamma release) was observed, as shown in FIG.5.

[0269] NCI-H441, NCI-H2087, and OVCAR3 cancer cell-lines were pre-treated for 5 days with 75nM decitabine in tissue culture medium, or tissue culture medium alone (untreated), then used as target cells in an IFNγ ELISPOT assay with healthy donor PBMCs and a titration of PRAME ImmTAC molecule.

[0270] Multimodal Therapy

[0271] Combinations of biologics (e.g., pembrolizumab, bevacizumab) and chemotherapies are standard of care in early-line advanced non-small cell lung cancer (NSCLC), ovarian cancer (OC), and endometrial cancer (EC). The potential benefit of the application of multimodal therapy in earlier lines of therapy (e.g., first-line) for advanced disease relative to later lines of therapy include: the potential for smaller tumor burden (Kim, Cassella, and Byrne 2021), decreased likelihood of therapeutic resistance (Long et al.2019), and improved PFS (Bailey et al.2012).

[0272] Clinical Trial Modules and Combination ArmsAtty. Docket No.0282-0009WO2

[0273] A summary view of the different combination therapies and associated tumor modules are shown in FIG.6 and Table A. Table A Intervention Type Dose Strength( Dose Route of Use Formulatio s) Level(s) Administrati n and on Frequenc y IMC-F106C Biologic Concentrate 0.20 Doses of IV infusion Experiment (All) (sTCR:scFv for solution mg / mL 0.2 to 320 al fusion for infusion mcg QW protein) have been assessed; option to assess less frequent dosing Arm B: Checkpoint Inhibitors (lung and ovarian / uterine) pembrolizum Biologic Concentrate 25 mg / mL 400 mg IV infusion Combinatio ab (B-2) (monoclonal for solution Q6W (200 n partner antibody) for infusion mg Q3W is also permissibl e) Arm C: Chemotherapy (lung, ovarian / uterine, and other tumor) gemcitabine Nucleoside Lyophilized Per local 1000 2 IV infusion Combinatio (C-1) metabolic powder for availabilit mg / m n partner inhibitor reconstitutio y (option to n or assess 750 solution for or 800 infusion mg / m2) 2 weeks on / 1 week off (3 weeks on / 1 week off also assessed) (Adamo et al.2008) nab-paclitaxel Microtubule Powder for Per local 100 mg / m2IV infusion Combinatio (C-2) inhibitor dispersion availabilit (option to n partner for infusion y assess 275 mg / m), 3 weeks on / Atty. Docket No.0282-0009WO2 Intervention Type Dose Strength( Dose Route of Use Formulatio s) Level(s) Administrati n and on Frequenc y 1 week off, or 2 weeks on / 1 week off (QW also assessed) PLD (C-3) Anthracyclin Concentrate Per local 50 mg / m2IV infusion Combinatio e for solution availabilit Q4W (may n partner topoisomera for infusion y reduce to se inhibitor 55 or 60 mg / m2Q4W) docetaxel (C- Microtubule Concentrate Per local 75 mg / m2IV infusion Combinatio 4) inhibitor for solution availabilit Q3W n partner for infusion y carboplatin Platinum Concentrate Per local AUC 6 IV infusion Combinatio (C-5) coordination for solution availabilit Q3W (may n partner compound for infusion y reduce to AUC5 Q3W or adjust to AUC 2, 2 weeks on / 1 week off) paclitaxel (C- Microtubule Concentrate Per local 175 mg / m2IV infusion Combinatio 5) inhibitor for solution availabilit Q3W (may n partner for infusion y adjust to 80 mg / m2weekly) Arm D: Another ImmTAC (melanoma) tebentafusp Biologic Concentrate 100 20 mcg on IV infusion Combinatio (D-1) (sTCR: scFv for solution mcg / 0.5 1st week, n partner fusion for infusion mL 30 mcg on protein) 2nd week, 68 mcg on 3rd week and QW thereafter Arm E: Targeted Therapy (lung, ovarian / uterine and melanoma)Atty. Docket No.0282-0009WO2 Intervention Type Dose Strength( Dose Route of Use Formulatio s) Level(s) Administrati n and on Frequenc y bevacizumab Biologic Concentrate Per local 15 mg / kg IV infusion Combinatio (E-1) (monoclonal for solution availabilit Q3W n partner antibody) for infusion y osimertinib Kinase Tablets 80 mg and 80 mg QD Oral Combinatio (E-2) inhibitor 40 mg n partner dabrafenib Kinase Capsules 50 mg and 150 mg Oral Combinatio (E-3) inhibitor 75 mg twice daily n partner trametinib (E- Kinase Tablets 0.5 mg 2 mg once Oral Combinatio 3) inhibitor and 2 mg daily n partner Arm F: Hypomethylating Agents (other tumor) low-dose Nucleoside Lyophilized Per local 0.07, 0.2, IV infusion or Combinatio decitabine (F- metabolic powder for availabilit or 0.6 SC injection n partner 1) inhibitor reconstitutio y mg / kg n QW (may assess less frequent dosing) Arm G: Multimodal (lung and ovarian / uterine) carboplatin Platinum Concentrate Per local AUC 6 IV infusion Combinatio (G-1) coordination for solution availabilit Q3W (may n partner compound for infusion y adjust to AUC 5 Q3W) paclitaxel (G- Microtubule Concentrate Per local 200 mg / m2IV infusion Combinatio 1) inhibitor for solution availabilit Q3W (may n partner for infusion y assess 2175 mg / m Q3W 2 or 80 mg / m weekly) pembrolizum Biologic Concentrate 25 mg / mL 400 mg IV infusion Combinatio ab (G-1) (monoclonal for solution Q6W (200 n partner antibody) for infusion mg Q3W is also permissibl e)Atty. Docket No.0282-0009WO2 Intervention Type Dose Strength( Dose Route of Use Formulatio s) Level(s) Administrati n and on Frequenc y carboplatin Platinum Concentrate Per local AUC 4 IV infusion Combinatio (G-2) coordination for solution availabilit Q3W (may n partner compound for infusion y adjust to AUC 3 Q3W) gemcitabine Nucleoside Lyophilized Per local 1000 2 IV infusion Combinatio (G-2) metabolic powder for availabilit mg / m n partner inhibitor reconstitutio y (option to n or assess 750 solution for or 800 infusion mg / m2) 2 weeks on / 1 week off bevacizumab Biologic Concentrate Per local 15 mg / kg IV infusion Combinatio (G-2) (monoclonal for solution availabilit Q3W n partner antibody) for infusion y carboplatin Platinum Concentrate Per local AUC 5 or IV infusion Combinatio (G-3) coordination for solution availabilit AUC 6 n partner compound for infusion y Q3W (up to 4 doses) pemetrexed Folate Powder, Per local 500 mg / m2IV infusion Combinatio (G-3) analog lyophilized, availabilit n partner metabolic for solution y Q3W (up inhibitor for to 4 doses) intravenous use pembrolizum Biologic Concentrate 25 mg / mL 400 mg IV infusion Combinatio ab (G-3) (monoclonal for solution Q6W (200 n partner antibody) for infusion mg Q3W is also permissibl e) REFERENCES Awada, Hassan, Reda Z. 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Claims

Atty. Docket No.0282-0009WO2 CLAIMS What is claimed is:

1. A method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen; wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose; and wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule.

2. The method of claim 1, wherein the second active agent is a chemotherapeutic agent.

3. The method of claim 2, wherein the chemotherapeutic agent is gemcitabine.Atty. Docket No.0282-0009WO2 4. The method of claim 2, wherein the chemotherapeutic agent is docetaxel.

5. The method of claim 1, wherein the second active agent is a targeted therapy.

6. The method of claim 5, wherein the targeted therapy is osimertinib.

7. The method of claim 1, wherein the second active agent is a multi-modal therapy.

8. The method of claim 7, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

9. The method of claim 7, wherein the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

10. A method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; andAtty. Docket No.0282-0009WO2 wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose; and wherein the second active agent is administered at least once prior to, concurrent with, and / or after the first dose comprising the TCR-anti-CD3 antibody fusion molecule.

11. The method of claim 10, wherein the second active agent is a chemotherapeutic agent.

12. The method of claim 11, wherein the chemotherapeutic agent is gemcitabine.

13. The method of claim 11, wherein the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD).

14. The method of claim 11, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

15. The method of claim 10, wherein the second active agent is a targeted therapy.

16. The method of claim 15, wherein the targeted therapy is bevacizumab.

17. The method of claim 10, wherein the second active agent is a multi-modal therapy.

18. The method of claim 17, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

19. The method of claim 17, wherein the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

20. The method of any one of claims 1 to 19, wherein the first dose comprises 2 to 4 ug of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 5 to 14 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 15 to 55 µg of the TCR-anti-CD3 antibody fusion molecule.

21. The method of claim 20, wherein the first dose comprises 3 ug of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 10 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 40 µg of the TCR-anti-CD3 antibody fusion molecule.

22. The method of claim 1, wherein the first dose comprises 15 to 40 µg of the TCR-anti- CD3 antibody fusion molecule, the second dose comprises 30 to 80 µg of the TCR-anti-CD3Atty. Docket No.0282-0009WO2 antibody fusion molecule, and the maintenance dose comprises 140 to 200 µg of the TCR- anti-CD3 antibody fusion molecule.

23. The method of claim 22, wherein the first dose comprises 20 µg of the TCR-anti-CD3 antibody fusion molecule, the second dose comprises 40 µg of the TCR-anti-CD3 antibody fusion molecule, and the maintenance dose comprises 160 µg of the TCR-anti-CD3 antibody fusion molecule.

24. The method of any one of claims 1 to 23, wherein the alpha chain amino acid sequence has 100% identity to the amino acid sequence of SEQ ID NO:

14.

25. The method of any one of claims 1 to 24, wherein the beta chain amino acid sequence has 100% identity to the amino acid sequence of SEQ ID NO:

16.

26. The method of any one of claims 1 to 25, wherein the first dose is administered once every 7 days.

27. The method of any one of claims 1 to 25, wherein the first dose is administered for 1 week to about 3 weeks.

28. The method of claim 27, wherein the first dose is administered for 1 week.

29. The method of any one of claims 1 to 28 wherein the second dose is administered 6 to 8 days following the first dose.

30. The method of any one of claims 1 to 29, wherein the second dose is administered once every 7 days.

31. The method of any one of claims 1 to 30, wherein the second dose is administered for 1 week to about 3 weeks.

32. The method of claim 31, wherein the second dose is administered for 1 week.

33. The method of any one of claims 1 to 32, wherein the maintenance dose in the first phase is administered 6 to 8 days following the second dose.

34. The method of any one of claims 1 to 33, wherein the maintenance dose in the first phase is administered once in a week.Atty. Docket No.0282-0009WO2 35. The method of any one of claims 1 to 34, wherein the first phase is about 2 weeks to about 101 weeks.

36. The method of claim 35, wherein the first phase is about 8 weeks to about 14 weeks.

37. The method of claim 36, wherein the first phase is 10 weeks.

38. The method of any one of claims 1 to 37, wherein the maintenance dose in the second phase is administered once every 2 weeks.

39. The method of any one of claims 1 to 38, wherein the second phase is about 30 weeks to 50 weeks.

40. The method of claim 39, wherein the second phase is 38 weeks.

41. The method of any one of claims 1 to 40, wherein the maintenance dose in the third phase is administered every 4 weeks.

42. The method of any one of claims 1 to 41, wherein the third phase is about 40 weeks to about 60 weeks.

43. The method of claim 42, wherein the third phase is about 48 weeks.

44. The method of any one of claims 1 to 43, wherein the first phase is 10 weeks, the second phase is 38 weeks, and the third phase is 48 weeks.

45. The method of any one of claims 1 to 44, wherein the first dose is administered for 1 week, the second dose is administered for 1 week, and the maintenance dose is administered for at least 40 weeks.

46. The method of any one of claims 1 to 45, wherein the dosing regimen is about 90 weeks to about 110 weeks.

47. The method of any one of claims 1 to 46, wherein no corticosteroids are administered within three weeks prior to the dosing regimen and throughout the dosing regimen.

48. The method of any one of claims 1 to 47, wherein the subject is HLA-A*02 positive.

49. The method of any one of claims 1 to 48, wherein the subject is HLA-A*02:01 positive.Atty. Docket No.0282-0009WO2 50. The method of any one of claims 1 to 49, wherein the subject has BRAF V600 mutation.

51. The method of any one of claims 1 to 50, wherein the subject has been diagnosed with a life expectancy greater than 3 months.

52. The method of any one of claims 1 to 51, wherein the second active agent is co- administered with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

53. The method of any one of claims 1 to 51, wherein the second active agent is first administered 1 to 6 weeks prior to the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule.

54. The method of any one of claims 1 to 51, wherein the second active agent is administered 1 to 6 weeks after the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule.

55. The method of any one of claims 1 to 51, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule is administered after treatment with the second active agent is complete.

56. The method of any one of claims 1 to 55, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule.

57. The method of any one of claims 1 to 56, wherein the second active agent is administered for at least 10 weeks.

58. The method of claim 56, wherein the second active agent is administered for at least 40 weeks.

59. The method of claim 56, wherein the second active agent is administered for the duration of the dosing regimen.

60. The method of any one of claims 1 or 59, wherein the second active agent is gemcitabine.

61. The method of claim 60, wherein the gemcitabine is administered at about 750 to about 1000 mg / m2.Atty. Docket No.0282-0009WO2 62. The method of claim 60, wherein the gemcitabine is administered at a dose of about 1000 mg / m2.

63. The method of any one of claims 60 to 62, wherein the gemcitabine is administered once a week to once a month.

64. The method of any one of claims 60 to 63, wherein the gemcitabine is administered about (i) 4 weeks on and 1 week off, (ii) 3 weeks on and 1 week off, (iii) 2 weeks on and one week off, (iv) 1 week on and 1 week off, (v) weekly, or (vi) biweekly.

65. The method of any one of claims 1 to 59, wherein the second active agent is nab- paclitaxel.

66. The method of claim 65, wherein the nab-paclitaxel is administered at about 75 to about 100 mg / m2.

67. The method of claim 65, wherein the nab-paclitaxel is administered at a dose of about 100 mg / m2.

68. The method of any one of claims 65 to 67, wherein the nab-paclitaxel is administered once a week to once a month.

69. The method of any one of claims 65 to 68, wherein the nab-paclitaxel is administered about (i) 4 weeks on and 1 week off, (ii) 3 weeks on and 1 week off, (iii) 2 weeks on and one week off, (iv) 1 week on and 1 week off, (v) weekly, or (vi) biweekly.

70. The method of any one of claims 1 to 59, wherein the second active agent is decitabine.

71. The method of claim 70, wherein the decitabine is administered at about 0.07 to about 0.6 mg / kg.

72. The method of claim 70 or 71, wherein the decitabine is administered once a week to once a month.

73. The method of any one of claims 70 to 72, wherein the decitabine is administered about (i) once a week, (ii) once every two weeks, (iii) once every three weeks, or (iv) once every month.Atty. Docket No.0282-0009WO2 74. The method of any one of claims 1 to 59, wherein the second active agent is pegylated liposomal doxorubicin (PLD).

75. The method of claim 74, wherein the PLD is administered at about 40 mg / m2to 60 mg / m2every 4 weeks to every 6 weeks.

76. The method of any one of claims 1 to 75, wherein the composition is administered orally, subcutaneously, sublingually, intramuscularly, intravenously, intranasally, transdermally, or any combination thereof.

77. The method of any one of claims 1 to 76, wherein the second composition is administered orally, subcutaneously, sublingually, intramuscularly, intravenously, intranasally, transdermally, or any combination thereof 78. A method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 3 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 10 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and every week during the first phase, wherein the first phase is about 9 to 10 weeks,Atty. Docket No.0282-0009WO2 (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

79. A method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 3 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 10 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, andAtty. Docket No.0282-0009WO2 wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

80. A method of treating non-small or small cell lung cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 20 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 160 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and then every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule , during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosingAtty. Docket No.0282-0009WO2 regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

81. A method of treating ovarian carcinoma in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises: (i) administering one first dose comprising 20 µg of the TCR-anti-CD3 antibody fusion molecule, (ii) administering one second dose comprising 40 µg of the TCR-anti-CD3 antibody fusion molecule one week after the first dose, and (iii) administering a maintenance dose comprising 160 µg of the TCR-anti-CD3 antibody fusion molecule one week after the second dose, and then every week during the first phase, wherein the first phase is about 9 to 10 weeks, (iv) administering the maintenance dose every 2 weeks during the second phase, wherein the second phase is about 38 weeks, and (v) administering the maintenance dose every 4 weeks during the third phase, wherein the third phase is about 48 weeks, and wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.Atty. Docket No.0282-0009WO2 82. The method of any one of claims 78 to 81, wherein the second active agent is a chemotherapeutic agent.

83. The method of claim 82, wherein the chemotherapeutic agent is gemcitabine.

84. The method of claim 82, wherein the chemotherapeutic agent is docetaxel.

85. The method of any one of claims 78 to 81, wherein the second active agent is a targeted therapy.

86. The method of claim 85, wherein the targeted therapy is osimertinib.

87. The method of any one of claims 78 to 81, wherein the second active agent is a multi- modal therapy.

88. The method of claim 87, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

89. The method of claim 87, wherein the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

90. A kit comprising: (i) one first container comprising a first dose comprising 2 to 4 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 5 to 14 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 15 to 55 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose; (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, wherein the dosing regimen is specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering a maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; andAtty. Docket No.0282-0009WO2 (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

91. A kit comprising: (i) one first container comprising a first dose comprising 20 µg of a heterodimeric TCR-anti-CD3 antibody fusion molecule, (ii) one second container comprising a second dose comprising 40 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iii) one or more maintenance containers, each maintenance container comprising a maintenance dose comprising 160 µg of the heterodimeric TCR-anti-CD3 antibody fusion molecule, (iv) one or more containers comprising a second active agent dose; (v) instructions for administering the heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, wherein the dosing regimen is specified as (a) administering the first dose on week 1, (b) administering the second dose on week 2, (c) administering a maintenance dose weekly during the first phase for 10 weeks, (d) administering the maintenance dose every 2 weeks during the second phase for 38 weeks, and (e) administering the maintenance dose every 4 weeks during the third phase for 48 weeks; and (vi) instructions for administering the second active agent in a dosing regimen, wherein the dosing regimen is specified as (a) once weekly for two weeks and off one week, (b) once weekly for three weeks and off one week, or (c) once weekly for two weeks and off one week, in combination with the heterodimeric TCR-anti-CD3 antibody fusion molecule.

92. The kit according to claim 90 or 91, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity- determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acidAtty. Docket No.0282-0009WO2 sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively.

93. The kit according to any one of claims 90 to 92, wherein the kit comprises 2 to 10 maintenance containers.

94. The kit according to any one of claims 90 to 93, wherein the first dose, the second dose and / or the maintenance dose further comprise(s) a pharmaceutically acceptable excipient to form a first pharmaceutical formulation, second pharmaceutical formulation, and / or maintenance pharmaceutical formulation, respectively.

95. The kit according to claim 94, wherein the first, second and / or maintenance pharmaceutical formulation has a pH of about 6.5 to about 7.

5.

96. The kit of any one of claims 90 to 95, wherein the second active agent is a chemotherapeutic agent.

97. The kit of claim 96, wherein the chemotherapeutic agent is gemcitabine.

98. The kit of claim 97, wherein the dose amount of gemcitabine is 1000 mg / m2.

99. The kit of claim 96, wherein the chemotherapeutic agent is docetaxel.

100. The kit of claim 99, wherein the dose amount of docetaxel is 75 mg / m2.

101. The kit of claim 96, wherein the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD).

102. The kit of claim 96, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

103. The kit of any one of claims 90 to 95, wherein the second active agent is a targeted therapy.

104. The kit of claim 103, wherein the targeted therapy is osimertinib.

105. The kit of claim 104, wherein the dose amount of osimertinib is 80 mg.

106. The kit of claim 104, wherein the dose amount of osimertinib is 40 mg.

107. The kit of claim 103, wherein the targeted therapy is bevacizumab.Atty. Docket No.0282-0009WO2 108. The kit of any one of claims 90 to 95, wherein the second active agent is a multi-modal therapy.

109. The kit of claim 108, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

110. The kit of claim 109, wherein the dose amount of carboplatin is AUC 6.

111. The kit of claim 109 or 110, wherein the dose amount of paclitaxel is 200 mg / m2.

112. The kit of any one of claims 109 to 111, wherein the dose amount of pembrolizumab is 400 mg.

113. The kit of claim 108, wherein the multi-modal therapy is carboplatin / pemetrexed / pembrolizumab.

114. The kit of claim 113, wherein the dose amount of carboplatin is AUC 5.

115. The kit of claim 113, wherein the dose amount of carboplatin is AUC 6.

116. The kit of any one of claims 113 to 115, wherein the dose amount of pemetrexed is 500 mg / m2.

117. The kit of any one of claims 113 to 116, wherein the dose amount of pembrolizumab is 400 mg.

118. A method of treating a PRAME-positive cancer in a subject comprising administering to the subject a composition comprising (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule in a dosing regimen, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5Atty. Docket No.0282-0009WO2 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

119. The method of claim 118, wherein the PRAME-positive cancer is a non-small cell lung cancer or ovarian cancer.

120. A method of treating platinum-sensitive ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5Atty. Docket No.0282-0009WO2 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

121. The method of claim 120, wherein the second active agent is a targeted therapy.

122. The method of claim 121, wherein the targeted therapy is bevacizumab.

123. The method of claim 120, wherein the second active agent is a chemotherapeutic agent.

124. The method of claim 123, wherein the chemotherapeutic agent is gemcitabine.

125. The method of claim 123, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

126. The method of claim 123, wherein the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD).

127. The method of claim 120, wherein the second active agent is a multi-modal therapy.Atty. Docket No.0282-0009WO2 128. The method of claim 127, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

129. The method of claim 127, wherein the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

130. A method of treating platinum-resistant ovarian carcinoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosingAtty. Docket No.0282-0009WO2 regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

131. The method of claim 130, wherein the second active agent is a targeted therapy.

132. The method of claim 131, wherein the targeted therapy is bevacizumab.

133. The method of claim 131, wherein the second active agent is a chemotherapeutic agent.

134. The method of claim 133, wherein the chemotherapeutic agent is gemcitabine.

135. The method of claim 133, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

136. The method of claim 133, wherein the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD).

137. The method of claim 131, wherein the second active agent is a multi-modal therapy.

138. The method of claim 137, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

139. The method of claim 133, wherein the multi-modal therapy is carboplatin / gemcitabine / bevacizumab.

140. A method of treating non-small cell lung cancer in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering:Atty. Docket No.0282-0009WO2 (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.

141. The method of claim 140. wherein the second active agent is a chemotherapeutic agent.

142. The method of claim 141, wherein the chemotherapeutic agent is gemcitabine.

143. The method of claim 141, wherein the chemotherapeutic agent is docetaxel.

144. The method of claim 141, wherein the chemotherapeutic agent is pegylated liposomal doxorubicin (PLD).

145. The method of claim 141, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

146. The method of claim 140, wherein the second active agent is a targeted therapy.

147. The method of claim 146, wherein the targeted therapy is osimertinib.

148. The method of claim 140, wherein the second active agent is a targeted therapy.

149. The method of claim 148, wherein the targeted therapy is osimertinib.

150. The method of claim 148, wherein the targeted therapy is bevacizumab.Atty. Docket No.0282-0009WO2 151. The method of claim 140, wherein the second active agent is a multi-modal therapy.

152. The method of claim 151, wherein the multi-modal therapy is carboplatin / paclitaxel / pembrolizumab.

153. A method of treating melanoma in a subject comprising administering to the subject a composition comprising: (I) a heterodimeric TCR-anti-CD3 antibody fusion molecule, and (II) a second composition comprising a second active agent, in a dosing regimen, wherein the heterodimeric TCR-anti-CD3 antibody fusion molecule comprises (a) an alpha chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 14, and (b) a beta chain amino acid sequence that has at least 90%, at least 95% or 100% identity to the amino acid sequence of SEQ ID NO: 16, wherein the alpha chain comprises complementarity-determining regions (CDRs) comprising alpha chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 3, 4 and 5 respectively and the beta chain comprises beta chain CDRs 1, 2 and 3 having the amino acid sequences of SEQ ID NOs: 9, 10 and 11 respectively, wherein the dosing regimen comprises administering: (i) a first dose comprising 2 to 30 ug of the TCR-anti-CD3 antibody fusion molecule, (ii) a second dose comprising 5 to 60 µg of the TCR-anti-CD3 antibody fusion molecule, and (iii) a maintenance dose comprising 15 to 200 µg of the TCR-anti-CD3 antibody fusion molecule, wherein the maintenance dose is administered in at least three phases, wherein the first phase is administered once every 6 to 8 days, the second phase is administered once every 12 to 16 days, and the third phase is administered once every 26 to 30 days; and wherein the second dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the first dose, and the maintenance dose comprises a larger amount of the TCR-anti-CD3 antibody fusion molecule than the second dose, wherein the second active agent is administered 1 to 6 weeks prior to administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule, during the administration of the heterodimeric TCR-anti-CD3 antibody fusion molecule for the duration of the dosing regimen, and / or after the administration heterodimeric TCR-anti-CD3 antibody fusion molecule.Atty. Docket No.0282-0009WO2 154. The method of claim 153, wherein the second active agent is a second heterodimeric TCR-anti-CD3 antibody fusion molecule.

155. The method of claim 154, wherein the second heterodimeric TCR-anti-CD3 antibody fusion molecule is tebentafusp.

156. The method of claim 153, wherein the second active agent is a targeted therapy.

157. The method of claim 156, wherein the targeted therapy is dabrafenib / trametinib.

158. The method of claim 153, wherein the second active agent is a hypomethylating agent.

159. The method of claim 158, wherein the hypomethylating agent is decitabine.

160. The method of claim 158 or 159, wherein the hypomethylating agent is a low-dose decitabine.

161. The method of claim 153, wherein the second active agent is a chemotherapeutic agent.

162. The method of claim 161, wherein the chemotherapeutic agent is PLD.

163. The method of claim 161, wherein the chemotherapeutic agent is carboplatin / paclitaxel.

164. The method of any one of claims 1-9, 78, 80 or 82-89, wherein the lung cancer is non- small cell lung cancer (NSCLC), 165. The method of any one of claims 10-77, 79, 81, 82-89 or 119, wherein the ovarian carcinoma is platinum-sensitive ovarian carcinoma.

166. The method of any one of claims 10-77, 79, 81, 82-89 or 119, wherein the ovarian carcinoma is platinum-resistant ovarian carcinoma.

167. The kit of claims 90 or 91, wherein the second active agent dose is about 10-1000 mg / m2.

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