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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment that uses engineered T cells to target specific cancer cells. It combines T-cell receptor gene therapy with other drugs, such as CDX-1140 (an agonist anti-CD40) and Pembrolizumab (also known as KEYTRUDA), to enhance the immune system's ability to fight cancer. The main goal is to determine if this treatment is safe for individuals with incurable cancers. This trial may suit patients with advanced epithelial cancers who have been told their condition is incurable. 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, 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.

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

Research has shown that the treatments tested in this trial have been safe in past studies. For TCR-transduced T cells, research indicates they are generally safe and effective for both blood-related and solid tumors. Patients have tolerated them well, with serious side effects being uncommon.

CDX-1140, an antibody that boosts the immune system, has also demonstrated a good safety record in early studies. It did not cause high levels of cytokines, which is a positive sign for safety.

Pembrolizumab is a well-known cancer treatment with a long history of safe use. It has been used for years to treat various cancers, including lung cancer and melanoma. Its side effects are generally manageable and well-documented.

Overall, these treatments have been studied and appear safe, but note that this trial is still in its early stages. Researchers are primarily focused on ensuring the treatments are safe for use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TCR-transduced T-cell therapy because it offers a novel approach to cancer treatment by harnessing the power of the immune system. Unlike traditional treatments such as chemotherapy or radiation, which target cancer cells broadly, this therapy involves engineering T cells to specifically recognize and attack cancer cells. The combination of CDX-1140, TCR-T, and pembrolizumab aims to enhance this targeted immune response, potentially leading to more effective and personalized cancer therapy. This innovative mechanism of action could offer new hope for patients who do not respond to existing treatments.

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

Research has shown that using specially engineered immune cells, called TCR-transduced T cells, with the drug pembrolizumab holds promise for treating cancer. In this trial, participants will receive a combination of TCR-transduced T cells, pembrolizumab, and CDX-1140. Previous studies found that pembrolizumab, when combined with these engineered T cells, can help control tumor growth. CDX-1140, another treatment in this trial, is a protein that boosts the immune system and has demonstrated anti-tumor effects, especially when used with pembrolizumab. Evidence suggests that this combination is generally safe and may improve treatment outcomes for cancer patients. These findings support further exploration of this approach in clinical trials. ^{3 5 6 7 8}

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. 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 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 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

What Are the Treatments Tested in This Trial?

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.

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11208906/

Immune checkpoint inhibitors: breakthroughs in cancer ... The results of a phase I clinical trial (NCT02414269) support the combination of iCasp9M28z T cells with pembrolizumab (PD-1 mAb) for the treatment of malignant ...

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04520711/

Clinical Trial: NCT04520711 This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells (TCR-T) targeting tumor-specific antigens, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04520711

NCT04520711 | Hotspot TCR-T: A Phase I/Ib Study of ... The primary objective of this study is to determine the safety of the adoptive transfer of TCR-gene engineered T cells targeting TSA in combination with CD40 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8000216/

Agonistic CD40 Antibodies in Cancer Treatment - PMC Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1359610123000795

Harnessing the potential of CD40 agonism in cancer therapy Data from a phase I trial evaluating CDX-1140 with or without anti-PD-1 therapy (pembrolizumab) have shown a good safety profile at the dosage of 1.5 mg/kg ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11028348/

Development of CDX-1140, an agonist CD40 antibody for ... CDX-1140 does not promote cytokine production in whole blood assays and has good pharmacodynamic and safety profiles in cynomolgus macaques.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03329950

NCT03329950 | A Study of CDX-1140 (CD40) as ... This study will determine the MTD of CDX-1140 while also evaluating the safety, tolerability and efficacy of CDX-1140 alone (Part 1) or in combination with CDX- ...

8. aacrjournals.org aacrjournals.org/clincancerres/article/31/11/2079/762533/Facts-and-Hopes-of-CD40-Agonists-in-Cancer

Facts and Hopes of CD40 Agonists in Cancer Immunotherapy Whereas clinical trials show modest antitumor activity, some patients experience durable responses, especially when CD40 agonists are combined ...