Genetically Engineered T-Cells + Vaccine for Metastatic Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Steven A Rosenberg, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Pregnancy, Immunosuppression, Infections, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Background: Many cancer cells produce substances called antigens that are unique to each cancer. These antigens stimulate the body s immune responses. One approach to treating these cancers is to take disease-fighting white blood cells from a person, change those cells so they will target the specific proteins (called antigens) from the cancer cells, and return them to that person s blood. The use of the white blood cells in this manner is one form of gene therapy. A vaccine may help these modified white cells work better. Objective: To test a cancer treatment that uses a person s own modified white blood cells along with a vaccine that targets a specific protein. Eligibility: Adults aged 18 to 72 years with certain solid tumors that have spread after treatment. Design: Participants will undergo leukapheresis: Blood is removed from the body through a tube attached to a needle inserted into a vein. The blood passes through a machine that separates out the white blood cells. The remaining blood is returned to the body through a second needle. Participants will stay in the hospital for 3 or 4 weeks. They will take chemotherapy drugs for 1 week to prepare for the treatment. Then their modified white cells will be infused through a needle in the arm. They will take other drugs to prevent infections after the infusion. The vaccine is injected into a muscle; participants will receive their first dose of the vaccine on the same day as their cell infusion. Participants will have follow-up visits 4, 8, and 12 weeks after the cell infusions. They will receive 2 or 3 additional doses of the boost vaccine during these visits. Follow-up will continue for 5 years, but participants will need to stay in touch with the gene therapy team for 15 years. ...

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have completed any prior systemic therapy before enrolling.

What data supports the effectiveness of this treatment for metastatic cancer?

Research shows that genetically engineered T cells, like those used in this treatment, have been effective in targeting and reducing tumors in other cancers, such as pancreatic cancer and melanoma, by specifically recognizing and attacking cancer cells. ^{1 2 3 4 5}

Is the genetically engineered T-cell and vaccine treatment for metastatic cancer safe for humans?

Research shows that genetically engineered T-cells, like those used in cancer treatments, have been developed with methods that maintain low toxicity and high cell viability. While there are concerns about potential side effects, strategies are being developed to improve safety, such as integrating failsafe switches to manage toxicities. ^{1 2 5 6 7}

How is the treatment with genetically engineered T-cells and vaccine for metastatic cancer different from other treatments?

This treatment is unique because it uses T-cells that are genetically engineered to specifically target KRAS mutations, which are common in certain cancers. Unlike traditional treatments, this approach directly modifies the patient's own immune cells to enhance their ability to recognize and attack cancer cells, offering a personalized and potentially more effective therapy. ^{1 2 3 5 8}

Eligibility Criteria

This trial is for adults aged 18-72 with certain advanced solid tumors like urogenital, gastrointestinal, ovarian, colorectal, non-small cell lung, and breast cancers that have spread despite treatment. Participants must be able to undergo leukapheresis and stay in the hospital for about a month.

Inclusion Criteria

Participants must have serology results as follows:

Willing to sign a durable power of attorney

Participants must be co-enrolled on protocol 03-C-0277

Exclusion Criteria

Concurrent opportunistic infections

Any form of primary immunodeficiency

Clinically significant participant history which in the judgment of the Principal Investigator (PI) would compromise the participants ability to tolerate high-dose aldesleukin

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Preparation

Participants undergo leukapheresis to collect white blood cells, followed by a chemotherapy regimen to prepare for treatment

1 week

In-hospital stay for 3-4 weeks

Treatment

Participants receive genetically modified T-cells and a KRAS-targeted vaccine

12 weeks

Cell infusion on Day 0, vaccine doses at weeks 4, 8, and 12

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up visits at 4, 8, 12, and 20 weeks post-infusion, then every 3 months for 9 months, and every 6 months for 2 years

Long-term Follow-up

Participants maintain contact with the gene therapy team for extended monitoring

15 years

Treatment Details

Interventions

• Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations (CAR T-cell Therapy)
• Vaccine Directed Against KRAS Antigens (Cancer Vaccine)

Trial Overview The study tests a personalized cancer treatment combining modified white blood cells targeting specific proteins on cancer cells with a vaccine boosting this effect. Patients will receive chemotherapy before getting their engineered white cells back along with vaccine injections at set intervals.

Participant Groups

Group I: 1/ KRAS TCR + vaccine Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + KRAS TCR-Transduced PBL + high-dose aldesleukin + vaccine (Day 0, weeks 4 and 8 and at week 12 (if no progression)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

References

1. Germany pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012] A central role for T cells in the control of cancer has been supported by both animal models and clinical observations. Accordingly, the development of potent anti-tumor T cell immunity has been a long-standing objective of immunotherapy. Emerging data from clinical trials that test T cell immune-modulatory agents and genetically engineered and re-targeted T cells have begun to realize the profound potential of T cell immunotherapy to target cancer. This review will focus on a description of recent conceptual and technological advances for the genetic engineering of T cells to enhance anti-tumor T cell immunity through the introduction of tumor-specific receptors, both Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), as well as an overview of emerging data from ongoing clinical trials that highlight the potential of these approaches to effect dramatic and potent anti-tumor immunity.

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

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [2023] T cells with engineered KRAS G12D-specific TCRs mediated regression of metastases in a patient with pancreatic cancer.

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

Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. [2022] Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.

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

Genetically engineered T cells for the treatment of cancer. [2021] T-cell immunotherapy is a promising approach to treat disseminated cancer. However, it has been limited by the ability to isolate and expand T cells restricted to tumour-associated antigens. Using ex vivo gene transfer, T cells from patients can be genetically engineered to express a novel T cell receptor or chimeric antigen receptor to specifically recognize a tumour-associated antigen and thereby selectively kill tumour cells. Indeed, genetically engineered T cells have recently been successfully used for cancer treatment in a small number of patients. Here we review the recent progress in the field, and summarize the challenges that lie ahead and the strategies being used to overcome them.

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

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells. [2017] The use of human T lymphocytes genetically modified to express chimeric antigen receptors on their surfaces has emerged as a promising treatment strategy for malignant tumors. We have transfected primary human peripheral T lymphocytes with a recombinant vector carrying DNA fragments encoding anti-erbB2 scFv/Fc/CD28/CD3ζ chimeric antigen receptor using electroporation. Transfected T cells have been demonstrated to express anti-erB2 scFv/Fc on their surface and CD28/CD3ζ intracellularly. These modified T cells were able to specifically bind to erbB2 tumor-associated antigen on target tumor cells. After specific binding, modified T cells were activated to produce high levels of cytokines (not only interferon-γ but also interluekin-2) and mediate lysis of erbB2-positive human tumor cells in an antigen-specific manner. Furthermore, such genetically modified human T cells significantly delayed the growth of subcutaneous erbB2-positive human xenograft tumors after systemic administration. These preclinical studies suggest that human T cells can be modified genetically and redirected to tumors in cancer patients.

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

Cas9-induced targeted integration of large DNA payloads in primary human T cells via homology-mediated end-joining DNA repair. [2023] The reliance on viral vectors for the production of genetically engineered immune cells for adoptive cellular therapies remains a translational bottleneck. Here we report a method leveraging the DNA repair pathway homology-mediated end joining, as well as optimized reagent composition and delivery, for the Cas9-induced targeted integration of large DNA payloads into primary human T cells with low toxicity and at efficiencies nearing those of viral vectors (targeted knock-in of 1-6.7 kb payloads at rates of up to 70% at multiple targeted genomic loci and with cell viabilities of over 80%). We used the method to produce T cells with an engineered T-cell receptor or a chimaeric antigen receptor and show that the cells maintained low levels of exhaustion markers and excellent capacities for proliferation and cytokine production and that they elicited potent antitumour cytotoxicity in vitro and in mice. The method is readily adaptable to current good manufacturing practices and scale-up processes, and hence may be used as an alternative to viral vectors for the production of genetically engineered T cells for cancer immunotherapies.

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

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. [2018] Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms. In early clinical trials, CAR-T cell-based therapies achieved complete and durable responses in a significant proportion of patients. Despite clinical successes and given the side effect profiles of immunotherapies based on engineered cells, potential concerns with the safety and toxicity of various therapeutic modalities remain. We discuss the concerns associated with the safety and stability of the gene delivery vehicles for cell engineering and with toxicities due to off-target and on-target, off-tumor effector functions of the engineered cells. We then overview the various strategies aimed at improving the safety of and resolving toxicities associated with cell-based immunotherapies. Integrating failsafe switches based on different suicide gene therapy systems into engineered cells engenders promising strategies toward ensuring the safety of cancer immunotherapies in the clinic.

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

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation. [2021] Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS.