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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment using a person's own modified white blood cells (autologous T-cells genetically engineered to express receptors reactive against KRAS mutations) along with a vaccine targeting KRAS antigens to attack specific cancer proteins. The aim is to determine if this approach can effectively combat cancers with a KRAS mutation that have spread after standard treatments. Suitable candidates for this trial include individuals with certain solid tumors, such as colorectal, breast, or lung cancer, that did not respond to previous treatments and have metastasized. Participants will first receive chemotherapy to prepare their bodies, followed by their modified cells and a vaccine to enhance the cells' effectiveness. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

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

Research has shown that modifying a person's own T-cells to target KRAS mutations has been studied before. These studies found the treatment reasonably safe. For instance, a study on advanced pancreatic cancer patients using T-cells aimed at specific KRAS mutations showed the treatment was generally well-tolerated. Patients experienced some side effects, but these were expected and manageable.

Similarly, vaccines targeting KRAS have undergone research. A vaccine trial for pancreatic and colorectal cancers found the vaccine safe and effective in activating the immune system to fight cancer. Patients did not experience severe side effects, indicating the vaccine is tolerable.

Although this is a Phase 1 trial, which mainly focuses on safety, previous studies on these treatments offer some reassurance. The treatments have been tested before, and results suggest they are generally safe for people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional treatments for metastatic cancer, which often rely on broad chemotherapy or radiation, this investigational approach uses genetically engineered T-cells that specifically target KRAS mutations. These T-cells are designed to hunt down and attack cancer cells with these mutations, potentially offering a more precise and personalized treatment. Additionally, the inclusion of a vaccine aims to bolster the immune response, enhancing the body's ability to fight the cancer. Researchers are excited because this method could lead to more effective treatments with fewer side effects than conventional options.

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

Research has shown that specially engineered T-cells can effectively fight cancer by targeting specific changes, called KRAS mutations, in cancer cells. In this trial, participants will receive Autologous T-cells Genetically Engineered to Express Receptors Reactive Against KRAS Mutations. Early results suggest this method can help reduce cancer cells. Additionally, participants will receive a vaccine directed against KRAS antigens, which can strengthen the immune system and help the body produce more cancer-fighting cells. Studies have found that this vaccine can help the immune system recognize and attack cancer cells. Initial patient responses have been promising, with many showing specific immune reactions against cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Steven A Rosenberg, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06253520

Study Details | NCT06253520 | Autologous T-cells ... --Determine the safety and efficacy of administering autologous T cells transduced to express receptors targeting KRAS G12D or G12V mutations in conjunction ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03412877

NCT03412877 | Administration of Autologous T-Cells ... A Phase II study using the administration of autologous T-cells genetically engineered to express T-cell receptors reactive against neoantigens in patients ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5178827/

T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer Autologous peripheral-blood T cells were genetically engineered to express each of the indicated KRAS G12D–reactive T-cell receptors that ...

4. cell.com cell.com/cancer-cell/fulltext/S1535-6108(25)00215-6

Mutant KRAS peptide targeted CAR-T cells engineered for ... Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT06253520

National Cancer Institute (NCI) Autologous T-cells genetically engineered to express receptors reactive against KRAS mutations in conjunction with a vaccine directed against these antigens.

6. trialx.com trialx.com/clinical-trials/listings/272613/mutant-kras-g12v-specific-tcr-transduced-t-cell-therapy-for-advanced-pancreatic-cancer/

Mutant KRAS G12V-specific TCR Transduced T Cell ... This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients.

7. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/autologous-kras-mutant-specific-tcrs-gene-engineered-pbls

Clinical Trials Using Autologous KRAS Mutant-specific ... Review the clinical trials studying autologous kras mutant-specific tcrs gene engineered pbls on this list and use the filters to refine the results by age ...