KK-LC-1 TCR Gene Therapy for Cancer

Overseen By Monica E Epstein, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, others

Disqualifiers: Autoimmune diseases, HIV, Hepatitis, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new cancer treatment that uses patients' own immune cells to fight cancer. The treatment modifies T cells (a type of white blood cell) to target a specific protein, KK-LC-1, found in certain cancers such as gastric, breast, cervical, and lung cancers. This approach is known as KK-LC-1 TCR Gene Therapy. The main goal is to determine if this treatment is safe for individuals with advanced or hard-to-treat cancers that express KK-LC-1. Participants must have a confirmed KK-LC-1 positive cancer that hasn't responded well to other treatments. 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 for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, more than four weeks must have passed since any prior systemic therapy before receiving the KK-LC-1 TCR T cells. Participants on active systemic immunosuppressive therapy that cannot be safely withheld are excluded from the trial.

Is there any evidence suggesting that KK-LC-1 TCR Gene Therapy is likely to be safe for humans?

Research has shown that treatments like KK-LC-1 TCR T cell therapy hold promise in fighting various cancers, including melanoma and synovial cell sarcoma. Past studies have reported varying levels of patient response to these therapies. The current study tests the safety of using different doses of KK-LC-1 TCR T cells in combination with aldesleukin.

Aldesleukin extends the lifespan of the modified T cells in the body, potentially enhancing the treatment's effectiveness against cancers with the KK-LC-1 marker. Although specific safety data for KK-LC-1 TCR T cells is not yet available, the study is in its early stages, focusing on ensuring participant safety.

Overall, similar treatments have generally been well-tolerated, but participants will be closely monitored for any side effects. The study aims to determine the optimal dose to minimize risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard cancer treatments, which often involve chemotherapy or radiation, KK-LC-1 TCR gene therapy is unique because it harnesses the power of the immune system to fight cancer. This therapy uses T cells engineered to target KK-LC-1, a specific protein found in certain cancer cells. Researchers are excited about KK-LC-1 TCR because it offers a targeted approach, potentially reducing harm to healthy cells and minimizing side effects. Additionally, this therapy includes aldesleukin, which enhances the activity of T cells, possibly improving the treatment's effectiveness against cancer.

What evidence suggests that KK-LC-1 TCR Gene Therapy could be an effective treatment for KK-LC-1 positive cancers?

Research has shown that a new treatment called T Cell Receptor (TCR) gene therapy might help treat certain cancers. This therapy targets a protein called KK-LC-1, found in some cancer cells, including those in the stomach, breast, cervix, and lungs. In this trial, participants will receive KK-LC-1 TCR T cells, which studies have demonstrated can effectively find and destroy cancer cells with this protein. Early results suggest that these modified T cells can attack cancer cells without harming normal cells. While more research is needed, this method could become a new treatment option for patients with cancers that have the KK-LC-1 protein. ^{1 2 3 4 6}

Who Is on the Research Team?

Scott M Norberg, D.O.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with certain advanced KK-LC-1 positive epithelial cancers (like gastric, breast, cervical, lung) that have spread or are unresponsive to treatment. They must have normal organ function and no severe allergies to the trial drugs. Participants can't be on immunosuppressive therapy, have a compromised immune system or serious heart conditions.

Inclusion Criteria

Seronegative for HIV antibody, seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.

I agree to use birth control during and up to 4 months after the study, and I will take a pregnancy test if applicable.

My cancer is KK-LC-1 positive, confirmed by a test.

Exclusion Criteria

I am currently on immunosuppressive therapy that cannot be stopped safely.

I have a condition that significantly weakens my immune system.

Documented LVEF <= 45%.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Evaluation

Baseline evaluation including additional laboratory or imaging tests prior to treatment

1 week

Leukapheresis and Cell Growth

Leukapheresis procedure to collect T cells, followed by cell growth in the lab for 11-15 days

2-3 weeks

Chemotherapy

Participants receive chemotherapy to prepare for T cell infusion

1 week

Inpatient stay

T Cell Infusion and Aldesleukin Administration

Infusion of KK-LC-1 TCR T cells followed by aldesleukin administration for up to 4 days

1 week

Inpatient stay

Initial Recovery

Participants recover in the hospital until well enough to go home, usually 7-12 days post-infusion

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits at 40 days, 12 weeks, every 3 months for 3 visits, then every 6 months for 5 years

5 years

Multiple visits (in-person)

Long-term Follow-up

Participants are followed on a long-term gene therapy protocol with periodic blood tests and annual follow-ups for up to 15 years

15 years

What Are the Treatments Tested in This Trial?

Interventions

• Aldesleukin
• Cyclophosphamide
• Fludarabine
• KK-LC-1 TCR

Trial Overview The trial is testing T Cell Receptor Gene Therapy targeting KK-LC-1 antigen in cancer cells. It involves modifying patients' T cells to fight cancer and giving them back via injection after chemotherapy preparation and alongside a growth factor called aldesleukin.

How Is the Trial Designed?

Group I: Treatment at dose levels 1 through 7 Experimental Treatment 4 Interventions

Non-myeloablative, lymphocyte depleting preparative regimen, followed by KK-LC-1 TCR T cells plus aldesleukin at escalating doses

KK-LC-1 TCR is already approved in United States for the following indications:

Approved in United States as KK-LC-1 TCR-T for:

• Gastric cancer
• Breast cancer
• Cervical cancer
• Lung cancer
• Other KK-LC-1 positive epithelial cancers

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

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]

The use of TCR gene-modified T cells shows promise in treating hematological malignancies, as demonstrated in a human trial where these modified cells persisted long-term and reduced tumor burden in some patients.

Targeting the WT1 protein with TCR gene therapy has proven effective in eliminating leukemia cells in mouse models, and advancements in lentiviral TCR gene transfer aim to enhance safety and efficacy by improving TCR expression and reducing mis-pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. Stauss, HJ., Thomas, S., Cesco-Gaspere, M., et al.[2022]

T cell receptor-engineered T cell (TCR-T) therapy shows promise as a cancer treatment because it is not limited by the surface antigen expression of target cells, making it a potential option for solid tumors as well as hematologic malignancies.

However, the overall efficacy of TCR-T therapy in solid tumors remains lower compared to its success in blood cancers, highlighting the need to address specific barriers and develop strategies to enhance its effectiveness in these challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-T Immunotherapy: The Challenges and Solutions. Liu, Y., Yan, X., Zhang, F., et al.[2022]

TCR gene therapy is a promising alternative to traditional adoptive immunotherapy for cancer treatment, particularly in cases where isolating and expanding tumor-specific T cells is difficult.

Successful implementation of TCR gene therapy depends on factors such as TCR specificity, affinity, and the types of T cells used, which are crucial for enhancing the therapy's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rebalancing immune specificity and function in cancer by T-cell receptor gene therapy. Udyavar, A., Geiger, TL.[2021]

The TCRα-modified T cell product showed no signs of tumorigenic or mutagenic activity in vitro, indicating that the viral vectors used for its generation are safe and do not cause genetic damage.

In mouse models, the adoptive transfer of TCRα-engineered T cells did not disrupt normal body functions and showed no acute toxicity or harmful immune reactions, suggesting a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. Kalinina, A., Bruter, A., Persiyantseva, N., et al.[2022]

T-cell receptor gene therapy shows promise in redirecting T lymphocytes to target tumors, leading to encouraging clinical responses in previously incurable cancers, but it faces significant challenges in ensuring safety and efficacy.

Identifying specific tumor epitopes that can effectively target cancer cells while avoiding damage to normal tissues is crucial, and there is a need for improved preclinical methods to assess potential risks associated with this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy--ready to go viral? Karpanen, T., Olweus, J.[2021]

T-cell receptor (TCR) gene therapy has shown promise in redirecting T cells to target and eliminate cancer cells, demonstrating effective cytotoxic and helper T cell responses in both laboratory and human studies.

Recent advancements in modifying TCRs and improving vector delivery systems aim to enhance the safety and efficiency of TCR gene transfer, making it a potentially powerful tool in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. Thomas, S., Hart, DP., Xue, SA., et al.[2019]

A systematic review of 19 clinical trials involving 231 patients found that the most common lymphodepleting (LD) regimen before TCR-T therapy was cyclophosphamide and fludarabine, but higher doses led to increased rates of febrile neutropenia without significantly improving treatment responses.

There is a significant lack of safety data in current studies, highlighting the need for standardized reporting guidelines to better assess the risks and benefits of different LD regimens in TCR-T therapy for advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphodepleting chemotherapy practices and effect on safety and efficacy outcomes in patients with solid tumours undergoing T cell receptor-engineered T cell (TCR-T) Therapy: a systematic review and meta-analysis. Owen, K., Ghaly, R., Shohdy, KS., et al.[2023]

Irradiation-induced host conditioning is more effective than vaccine-induced activation for enhancing the effectiveness of TCR-modified T cells in targeting tumors.

Optimizing TCR expression and ensuring a high precursor frequency of TCR-modified T cells are crucial for improving their antitumor activity, suggesting that TCR gene therapy can effectively apply pressure on tumors to express multiple antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Requirements for effective antitumor responses of TCR transduced T cells. de Witte, MA., Jorritsma, A., Kaiser, A., et al.[2019]

T cell receptors (TCRs) are being developed as a promising class of cancer therapies that can specifically target proteins expressed by cancer cells, including neoantigens and viral oncoproteins, enhancing the immune response against tumors.

Current clinical data show that TCR-based therapies, such as adoptive cell transfer and TCR bispecific engagers, have demonstrated significant antitumor potential across various human cancers, although challenges like HLA restriction and cross-reactivity remain in their development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. Klebanoff, CA., Chandran, SS., Baker, BM., et al.[2023]

Transfecting K1735 melanoma cells with both MHC class I (Kk) and class II (Ak) molecules led to tumor rejection in normal C3H mice, indicating that both types of antigen presentation are crucial for effective anti-tumor immunity.

The study found that the presence of CD4+ and CD8+ T cells is necessary for tumor rejection, and that IL-2 can substitute for MHC class II in promoting immune response, highlighting the complex interplay between different immune components in fighting tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rejection of K1735 murine melanoma in syngeneic hosts requires expression of MHC class I antigens and either class II antigens or IL-2. Chen, PW., Ananthaswamy, HN.[2008]

Adoptive therapy using T-cell receptor (TCR)-engineered T cells shows promise for tumor treatment, but careful selection of target antigens and TCRs is crucial to minimize treatment-related side effects.

The study proposes a series of in vitro assays to assess the safety of TCRs, focusing on factors like target antigen expression in healthy tissues and potential cross-reactivity, which can help identify both on-target and off-target toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk. Kunert, A., Obenaus, M., Lamers, CHJ., et al.[2021]

CAR-T therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05035407

NCT05035407 | T Cell Receptor Gene Therapy Targeting ... The purpose of this study is to determine the safety of different doses of KK-LC-1 TCR T cells plus aldesleukin to treat metastatic or refractory/recurrent KK- ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05483491

NCT05483491 | KK-LC-1 TCR-T Cell Therapy for Gastric, ... This study will determine the MTD of KK-LC-1 TCR-T cells for the treatment of metastatic cancers that express KK-LC-1 and will assess clinical tumor response to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6712783/

Cancer targeting by TCR gene-engineered T cells directed ... T cell receptor (TCR) gene-engineered T cells have shown promise in the treatment of melanoma and synovial cell sarcoma, ...

4. aacrjournals.org aacrjournals.org/cancerres/article/81/13_Supplement/1496/667309/Abstract-1496-KK-LC-1-targeting-T-cell-receptor

Abstract 1496: KK-LC-1 targeting T cell receptor for adoptive T ... KK-LC-1 is a promising target for adoptive TCR cell therapy, and the 820TCR targeting KK-LC-1 is a highly potent and specific TCR with no observed off-target ...

5. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/302875

T Cell Receptor Gene Therapy Targeting KK-LC-1 for ... Objective: The purpose of this study is to determine the safety of different doses of KK-LC-1 TCR T cells plus aldesleukin to treat metastatic or refractory/ ...

6. withpower.com withpower.com/trial/phase-1-9-2021-df15a

KK-LC-1 TCR Gene Therapy for Cancer · Info for Participants Objective:The purpose of this study is to determine the safety of different doses of KK-LC-1 TCR T cells plus aldesleukin to treat metastatic or refractory/ ...