Customized TCR-T Cell Therapy for Cancer

Recruiting at19 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: TScan Therapeutics, Inc.

Must not be taking: Antiarrhythmics, Corticosteroids, Antimicrobials, others

Disqualifiers: Cardiac disease, Stroke, CNS metastases, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new cancer treatment where a patient's immune cells are modified to better fight their cancer. It focuses on patients with advanced solid tumors who have specific genetic markers. The modified cells are designed to recognize and attack cancer cells more effectively.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic corticosteroid therapy greater than 10 mg of prednisone daily within 7 days of enrollment, and you cannot receive another anti-cancer therapy concurrently.

What data supports the effectiveness of the treatment TSC-200-A0201, T-Plex, TSC-204-A0201, and TSC-204-C0702 for cancer?

Research shows that T-cell receptor (TCR) therapies, like those used in TSC-200-A0201 and TSC-204-A0201, can effectively target specific cancer antigens, leading to tumor regression in some cases. For example, TCR-engineered T cells targeting specific cancer markers have shown promise in treating breast cancer and colorectal cancer, suggesting potential effectiveness for similar therapies. ^{1 2 3 4 5}

What safety data exists for TCR-T cell therapy in humans?

TCR-T cell therapies have shown promise in treating cancer, but they come with safety concerns such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). In one study, a patient experienced mild cytokine release syndrome and another had severe encephalitis (brain inflammation). Another study reported a serious adverse event and fatal toxicity due to off-target effects on cardiac tissue. ^{6 7 8 9 10}

What makes the TCR-T cell therapy treatment unique for cancer?

This treatment is unique because it uses genetically engineered T cells with specific T-cell receptors (TCRs) that target tumor antigens, allowing for a personalized approach to attack cancer cells without harming normal tissues. It rapidly constructs TCR vectors from tumor samples, enabling efficient and tailored therapy for individual patients. ^{1 6 11 12 13}

Research Team

Dawn Pinchasik, MD

Principal Investigator

TScan Therapeutics

Eligibility Criteria

This trial is for adults with advanced solid tumors that can't be surgically removed or have spread, and who've tried all other treatments without success. They must match specific genetic markers (HLA types) and their cancer should express certain proteins (MAGE-A1/HPV16-E7). Good physical condition is required, they must understand the study, and not be on high-dose steroids or have serious heart issues.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer is advanced, cannot be surgically removed, and has not responded to standard treatments.

I have a solid tumor such as lung, skin, cervical, ovarian, anal, or genital cancer.

Exclusion Criteria

I have not taken more than 10 mg of prednisone daily in the last week.

I have not had a stroke or TIA in the last year.

I regularly need extra oxygen.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis

Participants undergo leukapheresis to collect cells for TCR-T product manufacturing

1 week

1 visit (in-person)

Lymphodepletion and Treatment

Participants undergo lymphodepletion and receive one or two doses of TCR-T cell therapy

4-6 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• TSC-200-A0201 (CAR T-cell Therapy)
• TSC-204-A0201 (CAR T-cell Therapy)
• TSC-204-A0201 + TSC-200-A0201 (CAR T-cell Therapy)
• TSC-204-A0201 + TSC-204-C0702 (CAR T-cell Therapy)
• TSC-204-C0702 (CAR T-cell Therapy)

Trial Overview The study tests personalized T cell therapies where patients' own immune cells are engineered to target cancer. It's an open-label trial meaning everyone knows what treatment they're getting. Participants will receive one of several therapy combinations after chemotherapy intended to prepare their body for the new cells.

Participant Groups

Group I: T-Plex Combination Cohort F + G Experimental Treatment 1 Intervention

TSC-201-B0702 + TSC-202-A0201

Group II: T-Plex Combination Cohort E + G Experimental Treatment 1 Intervention

TSC-204-A0101 + TSC-202-A0201

Group III: T-Plex Combination Cohort E + F Experimental Treatment 2 Interventions

TSC-204-A0101 + TSC-201-B0702

Group IV: T-Plex Combination Cohort D + G Experimental Treatment 1 Intervention

TSC-203-A0201 + TSC-202-A0201

Group V: T-Plex Combination Cohort D + F Experimental Treatment 1 Intervention

TSC-203-A0201 + TSC-201B0702

Group VI: T-Plex Combination Cohort D + E Experimental Treatment 1 Intervention

TSC-203-A0201 + TSC-204A0101

Group VII: T-Plex Combination Cohort C+ G Experimental Treatment 1 Intervention

TSC-200-A0201 + TSC-202-A0201

Group VIII: T-Plex Combination Cohort C + F Experimental Treatment 1 Intervention

TSC-200-A0201 + TSC-201B0702

Group IX: T-Plex Combination Cohort C + E Experimental Treatment 1 Intervention

TSC-200-A0201 + TSC-204-A0101

Group X: T-Plex Combination Cohort C + D Experimental Treatment 1 Intervention

TSC-200-A0201 + TSC-203-A0201

Group XI: T-Plex Combination Cohort B + G Experimental Treatment 1 Intervention

TSC-204-C0702 + TSC-202-A0201

Group XII: T-Plex Combination Cohort B + F Experimental Treatment 1 Intervention

TSC-204-C0702 + TSC-201B0702

Group XIII: T-Plex Combination Cohort B + E Experimental Treatment 1 Intervention

TSC-204-C0702 + TSC-204-A0101

Group XIV: T-Plex Combination Cohort B + D Experimental Treatment 1 Intervention

TSC-204-C0702 + TSC-203-A0201

Group XV: T-Plex Combination Cohort B + C Experimental Treatment 1 Intervention

TSC-204-C0702 and TSC-200-A0201

Group XVI: T-Plex Combination Cohort A + G Experimental Treatment 1 Intervention

TSC-204-A0201 + TSC-202-A0201

Group XVII: T-Plex Combination Cohort A + F Experimental Treatment 1 Intervention

TSC-204-A0201 + TSC-201-B0702

Group XVIII: T-Plex Combination Cohort A + E Experimental Treatment 1 Intervention

TSC-204-A0201 + TSC-204-A0101

Group XIX: T-Plex Combination Cohort A + D Experimental Treatment 1 Intervention

TSC-204-A0201 + TSC-203-A0201

Group XX: T-Plex Combination Cohort A + C Experimental Treatment 2 Interventions

TSC-204-A0201 and TSC-200-A0201

Group XXI: T-Plex Combination Cohort A + B Experimental Treatment 1 Intervention

TSC-204-A0201 and TSC-204-C0702

Group XXII: Monotherapy Cohort G Experimental Treatment 1 Intervention

TSC-202-A0201

Group XXIII: Monotherapy Cohort F Experimental Treatment 1 Intervention

TSC-201-B0702

Group XXIV: Monotherapy Cohort E Experimental Treatment 1 Intervention

TSC-204-A0101

Group XXV: Monotherapy Cohort D Experimental Treatment 2 Interventions

TSC-203-A0201

Group XXVI: Monotherapy Cohort C Experimental Treatment 1 Intervention

TSC-200-A0201

Group XXVII: Monotherapy Cohort B Experimental Treatment 1 Intervention

TSC-204-C0702

Group XXVIII: Monotherapy Cohort A Experimental Treatment 1 Intervention

TSC-204-A0201

Who Is Running the Clinical Trial?

TScan Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

1,400+

Findings from Research

The study successfully engineered T cell receptors (TCRs) specific for the cancer-testis antigen PLAC1, which is commonly expressed in breast cancer, showing that these TCR-engineered T cells can effectively target and destroy PLAC1-positive breast cancer cells in laboratory settings.

In mouse models, the PLAC1 TCR-transduced CD8+ T cells significantly delayed tumor progression, suggesting that targeting PLAC1 with engineered T cells could be a promising new approach for treating breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer. Li, Q., Liu, M., Wu, M., et al.[2020]

The study analyzed T cell receptor (TCR) diversity in blood and tumor samples from 9 patients with advanced colorectal cancer (CRC) treated with a combination of peptide vaccines and chemotherapy, revealing that TCR populations in tumors differ significantly from those in blood.

A decrease in TCR diversity in tumor tissues during treatment was associated with longer progression-free survival in some patients, suggesting that TCR diversity could serve as a predictive biomarker for the effectiveness of immunochemotherapy in advanced CRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the T cell repertoire by deep T cell receptor sequencing in tissues and blood from patients with advanced colorectal cancer. Tamura, K., Hazama, S., Yamaguchi, R., et al.[2020]

In a study analyzing the cytokine profiles of TCR T-cell therapy products, higher functionality of TNFα in CD8+ T cells and active phospho-STAT3 signaling were linked to better clinical responses in solid tumor treatments.

Conversely, profiles from CD4+ T-helper 2 cells were associated with poorer outcomes, suggesting that specific cytokine levels, such as IL15, Flt3-L, and CX3CL1, could serve as important biomarkers for predicting therapy effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion Product TNFα, Th2, and STAT3 Activities Are Associated with Clinical Responses to Transgenic T-cell Receptor Cell Therapy. Nowicki, TS., Peters, CW., Quiros, C., et al.[2023]

The study developed a novel immunotherapy using genetically engineered T cells that express a specific T-cell receptor (TCR) targeting melanoma-associated antigen (MAGE)-A4, which showed enhanced antitumor activity in both mice and a patient with uterine leiomyosarcoma.

By using small interfering RNA to downregulate the endogenous TCR, the modified T cells demonstrated improved surface expression of the tumor-specific TCR and increased effectiveness in killing tumor cells, suggesting a promising approach for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human. Sun, Q., Zhang, X., Wang, L., et al.[2021]

Genetically engineered T lymphocytes targeting carcinoembryonic antigen (CEA) led to significant reductions in serum CEA levels (74-99%) in three patients with metastatic colorectal cancer, with one patient showing a notable regression of cancer in the lungs and liver.

All patients experienced severe transient inflammatory colitis as a dose-limiting toxicity, highlighting both the potential efficacy and the risks associated with using CEA as a target in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Parkhurst, MR., Yang, JC., Langan, RC., et al.[2023]

T cell receptors (TCRs) are being developed as a promising class of cancer therapies that can specifically target proteins expressed by cancer cells, including neoantigens and viral oncoproteins, enhancing the immune response against tumors.

Current clinical data show that TCR-based therapies, such as adoptive cell transfer and TCR bispecific engagers, have demonstrated significant antitumor potential across various human cancers, although challenges like HLA restriction and cross-reactivity remain in their development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. Klebanoff, CA., Chandran, SS., Baker, BM., et al.[2023]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

A new T cell receptor mimic (TCRm) therapy targeting alpha-fetoprotein in hepatocellular carcinoma (HCC) demonstrated potent activity against cancer cells while showing no significant adverse effects in a safety assessment, indicating a promising safety profile.

In a clinical case, one patient with metastatic HCC achieved complete remission after nine months of treatment, highlighting the potential efficacy of this TCRm-based therapy in treating a cancer with limited existing options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma. Liu, C., Liu, H., Dasgupta, M., et al.[2022]

This study successfully used CRISPR-Cas9 technology to create personalized T cells that can target specific cancer mutations by knocking out the patients' own T cell receptors and inserting new, neoantigen-specific T cell receptors (neoTCRs).

In a phase I clinical trial involving 16 patients with refractory solid cancers, the engineered T cells showed the ability to persist in the body and traffic to tumors, although most patients experienced disease progression, highlighting the need for further research on efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-viral precision T cell receptor replacement for personalized cell therapy. Foy, SP., Jacoby, K., Bota, DA., et al.[2023]

The study developed an affinity-enhanced T cell receptor (TCR) targeting the MAGE A3 antigen for cancer therapy, which showed promising preclinical results with no off-target effects; however, it led to a serious adverse event in patients, indicating potential safety risks.

Post-adverse event investigations revealed that the TCR also recognized a peptide from the muscle protein Titin, suggesting that off-target recognition can occur in vivo, emphasizing the need for improved preclinical testing methods to prevent such toxicities in future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Cameron, BJ., Gerry, AB., Dukes, J., et al.[2023]

A new method was developed to create a library of T-cell receptors (TCRs) from frozen tumor biopsies, allowing for the rapid identification of TCR genes that target various tumor antigens, which is crucial for personalized cancer therapies.

When tested, T cells engineered with these tumor-specific TCRs showed strong antitumor effects in a tumor xenograft model, demonstrating the potential of this approach for effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Construction of Antitumor T-cell Receptor Vectors from Frozen Tumors for Engineered T-cell Therapy. Tsuji, T., Yoneda, A., Matsuzaki, J., et al.[2019]

A new synthetic T-cell receptor (TCR) targeting PD-L1 has been developed to enhance CAR-T therapy's effectiveness against solid tumors, addressing the issue of T-cell exhaustion caused by inhibitory molecules in the tumor environment.

In laboratory tests, the engineered TCRs demonstrated the ability to activate T cells and kill tumor cells, with the γ-TCRγδ variant showing superior effectiveness in an in vivo xenograft model compared to the δ-TCRγδ variant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-based binding domain fused to TCRγ chain facilitates T cell cytotoxicity for potent anti-tumor response. Chen, Z., Lin, C., Pei, H., et al.[2023]

Personalized TCR-T cell therapy, which uses T-cell receptors from tumor-specific T cells, shows significant therapeutic effects against patient-derived tumors, indicating its potential as an effective immunotherapy.

The presence of tumor-specific T cells, marked by CXCL13 expression, can predict how well a patient will respond to immune checkpoint blockade, highlighting their importance in antitumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response. He, J., Xiong, X., Yang, H., et al.[2023]

References

1. Greece pubmed.ncbi.nlm.nih.gov

PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer. [2020]

2. Greece pubmed.ncbi.nlm.nih.gov

Characterization of the T cell repertoire by deep T cell receptor sequencing in tissues and blood from patients with advanced colorectal cancer. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Infusion Product TNFα, Th2, and STAT3 Activities Are Associated with Clinical Responses to Transgenic T-cell Receptor Cell Therapy. [2023]

4. England pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Non-viral precision T cell receptor replacement for personalized cell therapy. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Rapid Construction of Antitumor T-cell Receptor Vectors from Frozen Tumors for Engineered T-cell Therapy. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Antibody-based binding domain fused to TCRγ chain facilitates T cell cytotoxicity for potent anti-tumor response. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response. [2023]