Personalized TCR-T Cell Therapy for Cancer

Overseen By Kim Sutcliffe, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Providence Health & Services

Must not be taking: Anti-CD40, Chemotherapy

Disqualifiers: Organ transplant, Pneumonitis, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: Until progression

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment that uses genetically engineered T cells to combat incurable cancers. It combines TCR-T cell therapy—an immunotherapy using T cells modified to better recognize cancer cells—with two other treatments to target cancer cells more effectively. The main goal is to determine the treatment's safety for patients. Individuals with advanced epithelial cancers that cannot be cured may be suitable for this trial, especially if their cancer has spread or is locally advanced. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot be on any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment within 21 days before starting the study treatment. Hormonal therapy for non-cancer-related conditions is allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier research showed that TCR-transduced T cells did not cause tumors or harmful DNA changes in lab tests, indicating they don't create new tumors or alter DNA dangerously. Other studies have found these cells safe for treating various cancers. However, one report noted a serious side effect, highlighting the importance of careful monitoring.

For pembrolizumab, studies involving thousands of patients have demonstrated a manageable safety profile. Common side effects include tiredness, muscle pain, rash, and fever, which are usually mild and treatable.

Both treatments have been used safely in other contexts, but close monitoring of participants in new trials remains crucial to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it uses a personalized TCR-T cell therapy approach for cancer, which is quite different from most standard treatments like chemotherapy and radiation. This therapy involves engineering a patient's own T cells to recognize and attack specific cancer cells, which could lead to a more targeted and potent immune response. Additionally, combining TCR-T cells with CDX-1140, a novel immune-stimulating antibody, and pembrolizumab, an established checkpoint inhibitor, may enhance the overall effectiveness by boosting the immune system's ability to fight cancer. This innovative combination aims to improve outcomes and potentially reduce side effects compared to traditional therapies.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that TCR-transduced T cells, a type of engineered immune cell, have potential in treating certain cancers. In a study with patients who had advanced cancer, these cells proved to be safe and effective. Specifically, TCR-T cells targeting a specific cancer marker showed positive results in treating melanoma and synovial sarcoma, with some patients experiencing a reduction in tumor size.

Pembrolizumab, which participants in this trial may receive alongside TCR-T cells and CDX-1140, has a proven track record. It is commonly used and has helped some cancer patients live longer, with a 5-year survival rate of up to 22% in certain cases. Combining these treatments might enhance their effectiveness against hard-to-treat cancers. ^{3 6 7 8 9}

Who Is on the Research Team?

Rom Leidner, MD

Principal Investigator

Providence Health & Services

Eric Tran, PhD

Principal Investigator

Providence Health & Services

Are You a Good Fit for This Trial?

This trial is for adults with advanced epithelial cancers deemed incurable, who have a life expectancy over 12 weeks and specific immune cells suitable for gene therapy. They must not be pregnant or planning pregnancy, agree to contraception, and have adequate organ function. Excluded are those with certain medical conditions, recent malignancies other than treated skin cancer or in situ carcinomas, severe heart disease, active infections like hepatitis B/C unless undetectable by qPCR, HIV-positive patients not on stable treatment, or anyone unable to follow the study protocol.

Inclusion Criteria

Patients known positive for HIV 1/2 antibodies, are eligible if ARV treatment compliant with documented stable absolute CD4 count > 300 cells/mm3 for at least 6 months and undetectable viral load.

I can take care of myself and am up and about more than half of my waking hours.

Laboratory values: WBC ≥ 2000/uL, Neutrophils ≥ 1000/uL, Hgb > 8.0 g/dl (patients may be transfused to reach this level), Platelets > 100,000 cells/mm3, Creatinine ≤ 2.0 mg/dL, AST & ALT ≤ 2.5 × ULN, Alkaline phosphatase ≤ 2.5 × ULN, Total bilirubin ≤ 2 × ULN (except patients with Gilbert's syndrome, who must have a total bilirubin ≤ 3.0 mg/dL). If total bilirubin is >1.5, conjugated bilirubin must be ≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN). If there is no institutional ULN, then conjugated bilirubin must be < 40% of total bilirubin.

Exclusion Criteria

I do not have severe heart problems or a history of heart attack or stroke in the last year.

I don't have lasting side effects from cancer treatment, except for possible hair loss or skin changes.

I do not have an active tuberculosis infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TCR-T cell infusion, followed by administration of PD-1 and CD40 monoclonal antibodies

Until progression

Clinic visits every 3 weeks for re-administration of antibodies

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of replication competent retrovirus (RCR) for the first year

1 year

Longitudinal evaluation of toxicities and immunological parameters

Optional Repeat Infusion

Option for repeat TCR-T infusion with potential preconditioning chemotherapy

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• TCR-transduced T cells

Trial Overview The trial tests TCR-transduced T cells combined with CDX-1140 (a CD40 agonist) and Pembrolizumab (PD-1 blockade) in patients with incurable cancers. It's a phase I/Ib study starting with safety assessments followed by efficacy evaluations using Simon's Two-Stage design to determine if these treatments can safely enhance the body's immune response against cancer.

How Is the Trial Designed?

Group I: CDX-1140 + TCR-T + Pembro Experimental Treatment 3 Interventions

Patients will receive CDX-1440, TCR-T, and pembrolizumab.

Who Is Running the Clinical Trial?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Providence Cancer Center, Earle A. Chiles Research Institute

Collaborator

Trials

21

Recruited

500+

Celldex Therapeutics

Industry Sponsor

Trials

66

Recruited

5,900+

Anthony S. Marucci

Celldex Therapeutics

Chief Executive Officer since 2008

MBA from Columbia University, MHL from Brown University

Diane C. Young

Celldex Therapeutics

Chief Medical Officer since 2019

MD from Harvard Medical School, AB in Biochemical Sciences from Harvard University

Published Research Related to This Trial

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., 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 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]

Adoptive transfer of tumor-reactive lymphocytes has shown success in treating metastatic melanoma, leading to the development of T cell receptor (TCR) gene engineering to enhance normal T cells' ability to target tumors.

Initial clinical studies indicate that TCR gene-engineered T cells can effectively mediate tumor regression in patients, showcasing the potential of this approach for treating melanoma and other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. Zhang, L., Morgan, RA.[2023]

The TCRα-modified T cell product showed no signs of tumorigenic or mutagenic activity in vitro, indicating that the viral vectors used for its generation are safe and do not cause genetic damage.

In mouse models, the adoptive transfer of TCRα-engineered T cells did not disrupt normal body functions and showed no acute toxicity or harmful immune reactions, suggesting a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. Kalinina, A., Bruter, A., Persiyantseva, N., et al.[2022]

T-cell receptor (TCR) gene-modified T cells can effectively cure mice with disseminated leukemia in a murine model of adoptive T-cell immunotherapy, showcasing the potential of this approach for treating human cancers.

To enhance the long-term effectiveness of TCR-modified T cells, activating these cells through their endogenous TCR can boost the expression of the introduced TCR, potentially leading to a stronger and more persistent antitumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR. Dossett, ML., Teague, RM., Schmitt, TM., et al.[2021]

In a study involving 3 melanoma patients undergoing adoptive cell transfer (ACT) with TCR-engineered T cells targeting the MART-1 antigen, researchers found that highly functional T cells play a crucial role in the antitumor immune response.

The study emphasizes the importance of developing strategies to sustain the functionality of these T cells over time to enhance the long-term effectiveness of TCR-engineered ACT immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. Ma, C., Cheung, AF., Chodon, T., et al.[2022]

T-cell receptor (TCR) gene therapy has shown promise in redirecting T cells to target and eliminate cancer cells, demonstrating effective cytotoxic and helper T cell responses in both laboratory and human studies.

Recent advancements in modifying TCRs and improving vector delivery systems aim to enhance the safety and efficiency of TCR gene transfer, making it a potentially powerful tool in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. Thomas, S., Hart, DP., Xue, SA., et al.[2019]

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]

T-cell receptor gene therapy shows promise in redirecting T lymphocytes to target tumors, leading to encouraging clinical responses in previously incurable cancers, but it faces significant challenges in ensuring safety and efficacy.

Identifying specific tumor epitopes that can effectively target cancer cells while avoiding damage to normal tissues is crucial, and there is a need for improved preclinical methods to assess potential risks associated with this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy--ready to go viral? Karpanen, T., Olweus, J.[2021]

Irradiation-induced host conditioning is more effective than vaccine-induced activation for enhancing the effectiveness of TCR-modified T cells in targeting tumors.

Optimizing TCR expression and ensuring a high precursor frequency of TCR-modified T cells are crucial for improving their antitumor activity, suggesting that TCR gene therapy can effectively apply pressure on tumors to express multiple antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Requirements for effective antitumor responses of TCR transduced T cells. de Witte, MA., Jorritsma, A., Kaiser, A., et al.[2019]

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