Engineered T-Cell Therapy for Lung Cancer

Overseen By Fred Hutch Intake

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids, Investigational agents, others

Disqualifiers: Organ transplant, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 58

Duration: Up to 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment designed to help the immune system combat lung cancer that has spread to other parts of the body. The treatment modifies a patient's own T cells (a type of immune cell) to better recognize and attack cancer cells. The study aims to determine the optimal dose and understand any side effects of this T-cell therapy, specifically using Autologous CD8+ and CD4+ Transgenic T Cells Expressing High Affinity KRASG12V Mutation-Specific T Cell Receptors (FH-A11KRASG12V-TCR). It seeks participants with metastatic solid tumors that have a specific KRASG12V mutation and who are willing to undergo procedures like tumor biopsies for research purposes. 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.

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

The trial requires a 'washout' period of at least two weeks from your last systemic treatment, such as immunotherapy or chemotherapy. For small molecules or investigational agents, you need to wait for at least five half-lives. However, there is no washout period for radiation, and bisphosphonates and denosumab are allowed. The protocol does not specify other medications, so you should discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications before starting treatment. You must be at least two weeks from your last systemic treatment, like immunotherapy or chemotherapy, and at least five half-lives from small molecule treatments. However, bisphosphonates and denosumab are allowed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that using a person's own specially modified T cells to fight cancer remains under study for safety. These T cells target a specific protein found on some cancer cells. As a Phase 1 study, the primary goal is to assess the safety of these cells for people.

In early studies with similar T cell treatments, some patients experienced side effects. These studies are crucial for determining the right dose that balances safety and effectiveness. Although detailed safety information for this specific treatment is not yet available, early trials prioritize safety, and researchers proceed with caution. This treatment is still in the early testing stages, and more information will be collected as the study progresses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about engineered T-cell therapy for lung cancer because it offers a targeted approach that differs from standard treatments like chemotherapy and immunotherapy. This therapy uses autologous CD8+ and CD4+ transgenic T cells specifically designed to target the KRASG12V mutation, a common driver in certain lung cancers. Unlike general treatments that can attack both cancerous and healthy cells, these engineered T cells aim to precisely attack cancer cells with minimal impact on normal tissues. This precision targeting has the potential to improve effectiveness and reduce side effects compared to conventional treatments.

What evidence suggests that this treatment might be an effective treatment for lung cancer?

Research has shown that new T cell receptor (TCR) therapies are promising in fighting cancer. In this trial, participants will receive a treatment using their own immune cells, called T cells, which are specially modified to better find and attack cancer cells with a specific change known as the KRAS G12V mutation. This mutation often appears in certain lung cancers, making it a key target for this approach. While early results are promising, consistent long-term benefits have not yet emerged. This treatment aims to enhance the immune system's ability to combat cancer, offering new hope for patients with advanced cancer. ^{1 2 3 4 5}

Who Is on the Research Team?

Elena Chiorean

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults with metastatic pancreatic, colorectal, or non-small cell lung cancers that have a specific KRAS G12V mutation. Participants must have tried or declined standard treatments and be in good overall health with proper organ function. They should not be pregnant, breastfeeding, planning to conceive soon, or have uncontrolled illnesses. A commitment to use effective contraception during the study and for 4 months after is required.

Inclusion Criteria

My cancer has a KRASG12V mutation.

I am 60 or older and my heart's pumping ability is at least 35%.

My kidneys work well enough (creatinine clearance >= 50 ml/min).

Exclusion Criteria

I have had a solid organ or bone marrow transplant.

I am on medication for an autoimmune disease.

I currently have an infection that is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis and Lymphodepletion Chemotherapy

Patients undergo leukapheresis and receive lymphodepletion chemotherapy with either cyclophosphamide and fludarabine or bendamustine

1 week

Multiple visits for chemotherapy administration

Treatment

Patients receive FHA11KRASG12V-TCR IV infusion on day 0, with potential additional infusion as soon as 28 days or up to 1 year after the first infusion

Up to 1 year

1 visit for initial infusion, additional visits for potential subsequent infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Follow-up visits on day 56, 112, 168, 224, 280, and 365

Long-term Follow-up

Participants are monitored long-term for up to 15 years

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Autologous CD8+ and CD4+ Transgenic T Cells Expressing High Affinity KRASG12V Mutation-Specific T Cell Receptors (FH-A11KRASG12V-TCR)

Trial Overview The trial tests genetically modified T cells designed to target cancer cells with the KRAS G12V mutation. Patients' own T cells are extracted and engineered to recognize this mutation before being reintroduced into their bodies. The goal is to see if these modified T cells can effectively attack the cancer cells in patients with advanced stages of certain cancers.

How Is the Trial Designed?

Group I: Treatment (FHA11KRASG12V-TCR) Experimental Treatment 12 Interventions

Patients undergo leukapheresis prior to treatment and receive lymphodepletion chemotherapy with either cyclophosphamide IV and fludarabine IV on days -6, -5, and -4, or bendamustine IV on days -4 and -3 at the discretion of the treating clinician and/or PI. Patients then receive FHA11KRASG12V-TCR IV on day 0. Patients may receive an additional FHA11KRASG12V-TCR IV infusion as soon as 28 days or up to 1 year after the first infusion. Patients undergo ECHO or MUGA during screening. Patients also undergo CT, PET or MRI as well as blood sample collection and a tissue biopsy at baseline and throughout the trial.

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Affini-T Therapeutics, Inc.

Industry Sponsor

Trials

3

Recruited

110+

Published Research Related to This Trial

KRAS mutations, particularly G12D and G12V, are common in pancreatic and colorectal cancers, making them promising targets for immunotherapy.

In a study using HLA-A*11:01 transgenic mice, T cells engineered to recognize these KRAS mutations significantly reduced tumor growth in a xenograft model, suggesting potential for effective treatment in human cancers with these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Wang, QJ., Yu, Z., Griffith, K., et al.[2019]

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]

The study identified a KRASG12V-specific TCR that effectively targets tumors in colorectal cancer, particularly through engineered CD4+ T cells, which showed significant tumor-killing efficacy in both in vitro and xenograft mouse models.

This TCR is particularly promising for the Chinese population as it recognizes specific HLA subtypes (HLA-DPB1*03:01 and DPB1*14:01), providing broader applicability for precision immunotherapy in treating solid tumors like pancreatic and colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors. Ai, Q., Li, F., Zou, S., et al.[2023]

A novel T cell receptor (TCR) targeting the Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) has been developed, showing effective recognition and regression of tumors expressing this antigen in preclinical models, particularly in epithelial cancers like gastric cancer.

The KK-LC-1 TCR-Ts demonstrated specificity for cancer cells without cross-reactivity to other human proteins, suggesting a potentially safe therapeutic option for treating epithelial malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1. Marcinkowski, B., Stevanović, S., Helman, SR., et al.[2021]

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) or TCR gene-modified T cells targeting mutant KRAS neo-antigens shows promise for treating advanced pancreatic ductal adenocarcinoma (PDAC), a cancer that has seen little progress in treatment for over 40 years.

To enhance the production of TILs specific to mutant KRAS, researchers developed a novel approach using tandem mini gene-modified autologous T cells (TMG-T) as artificial antigen-presenting cells, successfully generating TIL cultures that are specifically reactive to the mKRAS (G12V) mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of KRAS hotspot mutations reactive T cells from human pancreatic tumors using autologous T cells as the antigen-presenting cells. Wang, S., Zhang, X., Zou, X., et al.[2023]

Using CRISPR-Cas9 technology to specifically integrate an engineered TCR gene into the TCR alpha constant locus reduces the risk of insertional mutagenesis and mispairing with endogenous TCRs, enhancing the safety of T cell modifications.

This method not only successfully redirects the specificity of T cells in vitro but also demonstrates effective tumor rejection in an in vivo xenograft model, indicating strong potential for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. Albers, JJ., Ammon, T., Gosmann, D., et al.[2021]

T cell antigen receptor-engineered cytokine-activated T cells (TCR-CATs) can specifically target and kill cancer cells with high efficacy, showing good specificity and no off-target effects.

TCR-CATs demonstrated superior activation and cytotoxicity compared to traditional TCR-engineered T cells (TCR-Ts), making them a promising and potentially more cost-effective option for cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells. Kang, S., Li, Y., Bao, Y., et al.[2020]

Four KRAS-specific T-cell receptors (TCRs) were successfully isolated from a pancreatic cancer survivor, showing stable expression and functionality in T cells, indicating their potential for targeted cancer therapy.

These TCRs demonstrated the ability to recognize multiple KRAS mutations, suggesting that they could be effective in targeting a wide range of cancers with KRAS mutations, making them promising candidates for TCR-based immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. Dillard, P., Casey, N., Pollmann, S., et al.[2021]

The study successfully cloned a high-affinity T cell receptor (TCR) that specifically recognizes the KRAS G12V mutation, demonstrating its ability to target and kill various tumor cells in vitro, including PANC-1 and HeLa cells.

In vivo experiments showed that TCR-engineered T cells (KVA11-01 TCR-T) significantly inhibited tumor growth in mice without causing damage to healthy organs, indicating their potential as a safe and effective treatment for patients with KRAS G12V mutant solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preclinical study of T cell receptor specifically reactive with KRAS G12V mutation in the treatment of malignant tumors]. Cheng, XJ., Jiang, D., Zhang, LH., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.TPS792

Phase I study of autologous CD8+ and CD4+ transgenic T ... The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed with T cell receptor ( ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06043713

Study Details | NCT06043713 | Autologous CD8+ and ... This phase I trial studies the side effects and best dose of autologous CD8+ and CD4+ transgenic T cells expressing high affinity KRASG12V mutation-specific ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT475408

Phase I study of autologous CD8+ and CD4+ transgenic T ... Preliminary anti-tumor activity has been observed with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking.

4. clin.larvol.com clin.larvol.com/trial-detail/NCT06043713

Autologous CD8+ and CD4+ Transgenic T Cells ... Autologous CD8+ and CD4+ Transgenic T Cells Expressing High Affinity KRASG12V Mutation-Specific T Cell Receptors (FH-A11KRASG12V-TCR) in Treating Patients ...

5. alphaclinic.ucsf.edu alphaclinic.ucsf.edu/phase-i-study-autologous-cd8-and-cd4-engineered-t-cell-receptor-t-cells-subjects-advanced-or

Phase I Study of Autologous CD8+ and CD4+ Engineered T ... This study is open to adult patients with solid tumors who have a KRAS G12V mutation. This mutation is often found in non-small cell lung cancer (NSCLC) ...