Genetically Engineered T-Cells + Vaccine for Metastatic Cancer

Overseen By Steven A Rosenberg, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Pregnancy, Immunosuppression, Infections, others

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

Compensation: Varies

Number of Visits: 7

Duration: 12 weeks

210 Participants Needed

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}

Research Team

Steven A Rosenberg, M.D.

Principal Investigator

National Cancer Institute (NCI)

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

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
• Vaccine Directed Against KRAS Antigens

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)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

T cells play a crucial role in fighting cancer, and recent advances in immunotherapy are focusing on enhancing their effectiveness through genetic engineering.

The introduction of tumor-specific receptors, such as Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), shows promise in ongoing clinical trials, indicating a potential for strong anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Kalos, M.[2012]

Engineered T cells targeting the KRAS G12D mutation showed the ability to reduce metastases in a patient with pancreatic cancer, indicating a promising therapeutic approach.

This case highlights the potential of T cell receptor (TCR) engineering in specifically targeting cancer mutations, which could lead to more effective treatments for difficult-to-treat cancers like pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [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]

T-cell immunotherapy shows promise for treating widespread cancer by genetically engineering T cells to target tumor-associated antigens, allowing them to selectively kill cancer cells.

Recent successes in using genetically engineered T cells in a small number of patients highlight the potential of this approach, although challenges remain in isolating and expanding these T cells effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetically engineered T cells for the treatment of cancer. Essand, M., Loskog, AS.[2021]

Genetically modifying human T lymphocytes to express chimeric antigen receptors allows them to specifically target and bind to erbB2-positive tumor cells, leading to effective tumor cell lysis.

In preclinical studies, these modified T cells not only produced high levels of cytokines but also significantly delayed the growth of erbB2-positive tumors in human xenograft models, indicating a promising therapeutic strategy for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells. Wang, C., Hu, W., Shen, L., et al.[2017]

A new method for genetically engineering T cells using Cas9 technology allows for the targeted integration of large DNA sequences with up to 70% efficiency and over 80% cell viability, making it a promising alternative to traditional viral vector methods.

The engineered T cells maintained strong proliferation and cytokine production capabilities, and demonstrated effective anti-tumor activity in laboratory and mouse models, indicating their potential for use in cancer immunotherapy.

NCBI (Pubmed)

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. Webber, BR., Johnson, MJ., Skeate, JG., et al.[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]

Engineered T cells expressing a high-avidity T-cell receptor (TCR) specific for a unique amino acid substitution (AAS) in the p68 protein can effectively eradicate large, established solid tumors when the neoepitope is uniformly expressed by all cancer cells.

To prevent tumor escape from T-cell therapy, it is crucial to ensure high levels of the targeted neoepitope across all cancer cells or to combine T-cell therapy with additional treatments like local irradiation.

NCBI (Pubmed)

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. Leisegang, M., Engels, B., Schreiber, K., et al.[2021]

References

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

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. [2012]

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

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer. [2023]

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

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

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

Genetically engineered T cells for the treatment of cancer. [2021]

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

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells. [2017]

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]

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

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

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]