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

5 Participants Needed

Trial Summary

What is the purpose of this trial?

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 T cell receptors (FH-A11KRASG12V-TCR) and to see how well they work in treating patients with solid tumor cancers that has spread from where it first started (primary site) to other places in the body (metastatic). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this study will come from the patient and will have a new gene put in them that makes them able to recognize KRAS G12V, a protein on the surface of tumor cells. These KRAS G12V-specific T cells may help the body's immune system identify and kill KRAS G12V solid cancer tumor cells.

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.

What data supports the idea that Engineered T-Cell Therapy for Lung Cancer is an effective treatment?

The available research shows that Engineered T-Cell Therapy, specifically targeting KRAS mutations, has shown promise in treating various cancers. For example, T cells engineered to target KRAS mutations have been effective in reducing tumor growth in animal models, as seen in studies involving pancreatic and colorectal cancers. Additionally, T cells engineered to target specific cancer antigens have demonstrated the ability to recognize and attack cancer cells in laboratory settings. These findings suggest that this treatment could be effective for lung cancer as well, given its success in other cancers with similar mutations. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment for lung cancer?

Research shows that T cells engineered to target KRAS mutations, like the ones used in this treatment, have been effective in recognizing and attacking cancer cells in other types of solid tumors, such as pancreatic and colorectal cancers. These engineered T cells have demonstrated the ability to specifically target and kill tumor cells in laboratory and animal studies, suggesting potential effectiveness in treating lung cancer as well. ^{1 2 3 4 5}

What safety data is available for engineered T-cell therapy targeting KRASG12V mutations in lung cancer?

The safety data for engineered T-cell therapy targeting KRASG12V mutations is still emerging. Studies have shown that TCR-engineered T cells can effectively target KRASG12V mutations in vitro and in vivo, demonstrating tumor-killing effects. However, challenges such as HLA restriction and the rarity of TILs recognizing mutant KRAS limit the broad application of this therapy. Gene editing techniques like CRISPR-Cas9 are being explored to improve specificity and reduce risks like insertional mutagenesis. While promising, more clinical trials are needed to fully understand the safety profile of this therapy in lung cancer. ^{1 2 4 6 7}

What safety data exists for engineered T-cell therapy targeting KRASG12V mutations?

The research on engineered T-cell therapy targeting KRASG12V mutations suggests that these treatments have shown promise in preclinical studies for targeting specific cancer mutations, but there is limited information on safety in humans. The studies primarily focus on the effectiveness of these therapies in laboratory and animal models, and do not provide detailed safety data for human participants. ^{1 2 4 6 7}

Is the treatment FH-A11KRASG12V-TCR a promising treatment for lung cancer?

Yes, FH-A11KRASG12V-TCR is a promising treatment for lung cancer. It uses specially engineered T cells to target and kill cancer cells with a specific mutation called KRASG12V, which is common in many cancers. This approach has shown strong potential in research studies to effectively fight cancer by boosting the body's immune response. ^{1 2 3 8 9}

How is the FH-A11KRASG12V-TCR treatment different from other lung cancer treatments?

The FH-A11KRASG12V-TCR treatment is unique because it uses engineered T cells that specifically target the KRASG12V mutation, a common driver in many cancers, by using high-affinity T cell receptors (TCRs). This approach allows the immune system to precisely attack cancer cells with this mutation, offering a personalized and potentially more effective treatment option compared to traditional therapies. ^{1 2 3 8 9}

Research Team

Elena Chiorean

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting KRASG12V mutations with HLA class II-restricted TCR for the immunotherapy in solid tumors. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

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

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

Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors. [2021]

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

Cancer targeting by TCR gene-engineered T cells directed against Kita-Kyushu Lung Cancer Antigen-1. [2021]

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

Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. [2019]

6. Germany 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. [2023]

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

Gene editing enables T-cell engineering to redirect antigen specificity for potent tumor rejection. [2021]

8. China pubmed.ncbi.nlm.nih.gov

[Preclinical study of T cell receptor specifically reactive with KRAS G12V mutation in the treatment of malignant tumors]. [2022]

9. China pubmed.ncbi.nlm.nih.gov

High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells. [2020]