Engineered 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: Chemotherapy, Biologics, Hormonal therapy, others

Disqualifiers: Organ transplant, Pneumonitis, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 3

Duration: Until disease progression

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells (TCR-T) targeting tumor-specific antigens, with in vivo CD40 activation and PD-1 blockade, for patients with incurable cancers. The study design is a safety lead-in TCR-T with CD40/PD-1 (3+3), followed by Simon's Two-Stage expansion design, 80% power and 5% one-sided alpha: stage-one futility assessment at n = 10; stage-two assessment at n = 22, (accrual up to 24 to allow for potential study drop-out).

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does require that you have not received any investigational anticancer therapy recently and that you are not on any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of this treatment?

Research shows that engineered T cells, which are modified to better recognize and attack cancer cells, have been successful in treating certain types of cancer, like melanoma. These studies highlight the potential of TCR-engineered T cells to cause tumor regression and improve the immune response against cancer. ^{1 2 3 4 5}

What safety data exists for engineered T-cell therapy for cancer?

Engineered T-cell therapies, like CAR-T and TCR-T cells, have shown promise in treating cancer but come with safety concerns such as cytokine release syndrome (a severe immune reaction), neurotoxicity (nerve damage), and off-target effects (unintended effects on healthy cells). Preclinical studies in mice have shown no tumorigenic (cancer-causing) or mutagenic (mutation-causing) activity, and no acute toxicity, indicating potential safety in humans. ^{6 7 8 9 10}

How is the TCR-transduced T cells treatment different from other cancer treatments?

TCR-transduced T cells treatment is unique because it involves genetically engineering a patient's own T cells to specifically target and attack cancer cells, which can lead to a more precise and potentially more effective treatment compared to traditional therapies. This approach allows the engineered T cells to persist and expand in the body, offering a long-lasting immune response against cancer. ^{1 2 3 11 12}

Research Team

Eric Tran, PhD

Principal Investigator

Providence Health & Services

Rom Leidner, MD

Principal Investigator

Providence Health & Services

Eligibility Criteria

This trial is for adults with advanced epithelial cancers deemed incurable. Participants must have an ECOG performance status of 0-2, meet specific blood and organ function criteria, not be pregnant or breastfeeding, agree to contraception if applicable, and have a life expectancy over 12 weeks. They cannot join if they've had certain recent treatments or surgeries, other active cancers or severe illnesses that could interfere with the study.

Inclusion Criteria

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.

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.

Women of childbearing potential must have negative serum bHCG pregnancy test ≤ 24 hours prior to start of study treatment.

Exclusion Criteria

I had cancer before, but it was treated, hasn't come back in over a year, or was a non-threatening skin cancer or localized cancer that's gone now.

I am willing and able to follow the study's requirements.

Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TCR-T cell infusion, followed by CD40 and PD-1 blockade, with potential repeat TCR-T infusion and optional preconditioning chemotherapy

Until disease progression

Clinic visits every 3 weeks for re-administration of monoclonal antibodies

Follow-up

Participants are monitored for safety, effectiveness, and presence of replication competent retrovirus (RCR) for at least one year

1 year

Regular monitoring visits

Long-term follow-up

Participants are monitored for overall survival and duration of response

2 years

Treatment Details

Interventions

• CDX-1140
• Pembrolizumab
• TCR-transduced T cells

Trial Overview The trial tests TCR-transduced T cells targeting cancer antigens combined with CD40 activation (CDX-1140) and PD-1 blockade (Pembrolizumab). It's in early stages (Phase I/Ib), focusing on safety and determining the right dose. The design includes initial small groups followed by expansion based on interim results.

Participant Groups

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+

Findings from Research

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]

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]

Recent advancements in delivering transgenes to human T cells have improved the effectiveness of T cell therapies for cancer, allowing for the creation of T cells that can specifically target tumors.

While genetically modified T cells have shown success in clinical trials, they can also cause significant on-target toxicity, highlighting the need for careful selection of target antigens and strategies to manage potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered T cells for anti-cancer therapy. Turtle, CJ., Hudecek, M., Jensen, MC., et al.[2021]

T cell receptor (TCR) gene therapy shows promise in treating malignant tumors by enabling T cells to specifically target and respond to tumor cells.

To improve the effectiveness of TCR-engineered T cell therapy, it is crucial to select the right TCRs and develop strategies that enhance T cell movement and accumulation in tumor tissues, potentially leading to better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells to treat tumors: Seeing but not touching? Debets, R., Donnadieu, E., Chouaib, S., et al.[2021]

Adoptive cell transfer (ACT) using TCR-engineered T cells showed significant antitumor activity in mice with large tumors, especially when combined with lymphodepletion, dendritic cell vaccination, and high-dose IL-2.

The study utilized advanced imaging techniques to track T cell distribution and confirmed that these engineered T cells initially targeted antigen-matched tumors effectively, providing insights that could help translate this therapy for human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Koya, RC., Mok, S., Comin-Anduix, B., et al.[2022]

CAR-T cell therapies have shown significant clinical success in treating cancer by effectively targeting tumor-associated antigens, leading to complete and durable responses in many patients during early trials.

Despite their effectiveness, there are safety concerns regarding potential toxicities from engineered cells, prompting the exploration of strategies like integrating failsafe switches to enhance safety in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. Resetca, D., Neschadim, A., Medin, JA.[2018]

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 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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. [2023]

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

Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Engineered T cells for anti-cancer therapy. [2021]

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

TCR-engineered T cells to treat tumors: Seeing but not touching? [2021]

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

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. [2022]

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

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. [2018]

7. France pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. [2022]

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

T-cell receptor gene therapy--ready to go viral? [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

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

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

T cell tuning for tumour therapy: Enhancing effector function and memory potential of therapeutic T cells. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Challenges in T cell receptor gene therapy. [2023]

12. England pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. [2019]