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

100 Participants Needed

Trial Summary

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.

What data supports the idea that KK-LC-1 TCR Gene Therapy for Cancer is an effective treatment?

The available research shows that T-cell receptor (TCR) gene therapy, which includes KK-LC-1 TCR Gene Therapy, has shown promising results in treating certain cancers. For example, TCR gene therapy has been effective in reducing tumor size in some patients and has demonstrated strong antitumor effects in both laboratory and human studies. Additionally, TCR gene therapy can be more effective when combined with specific chemotherapy treatments, although these can have significant side effects. Overall, the research suggests that KK-LC-1 TCR Gene Therapy can be a powerful tool in fighting cancer, especially when other treatments are not effective. ^{1 2 3 4 5}

What safety data is available for KK-LC-1 TCR gene therapy for cancer?

The safety data for KK-LC-1 TCR gene therapy includes preclinical studies showing no tumorigenic or mutagenic activity in vitro, no acute toxicity or immunotoxicity in vivo, and no pathological changes in organs due to T cell accumulation. Cross-reactivity studies did not demonstrate cross-reactivity against other human proteins, and CT83 gene expression was restricted to germ cells, with expression noted in various epithelial cancers. These findings support further investigation and clinical testing of KK-LC-1 TCR-Ts for cancer treatment. ^{6 7 8 9 10}

Is the KK-LC-1 TCR treatment a promising treatment for cancer?

Yes, the KK-LC-1 TCR treatment is promising because it uses T cell receptors to target cancer cells specifically, which can help reduce tumors and improve the immune system's ability to fight cancer. ^{1 2 11 12 13}

What is the purpose of this trial?

Background: Researchers have found a new way to treat cancer using T cell therapy. The therapy used in this study is T Cell Receptor (TCR) Gene Therapy Targeting KK-LC-1, a cancer germline antigen that is expressed by certain cancers. This therapy is a type of treatment in which a participant s T cells (a type of immune system white blood cell) are changed in the laboratory to attack cancer cells and given back to the participant. This treatment might help people with KK-LC-1 positive cancers which may include gastric, breast, cervical, lung and other epithelial Cancers. Epithelial cancers are cancers that begin in the cells that line an organ. 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/recurrent KK-LC-1 positive cancers. Eligibility: Adults aged 18 and older with metastatic or refractory/recurrent KK-LC-1 positive epithelial cancer. Design: Participants will be screened with HLA typing (a blood test needed for eligibility) and KK-LC-1 testing of the cancer tumor (to determine if the cancer is KK-LC-1 positive). A new biopsy may be needed if tumor from an outside location is not available for KK-LC-1 testing. Eligible participants will come to the NIH campus to have a screening evaluation which will include physical exam, review of medical history and current medications, blood and heart tests, imaging (X-ray, CT scan, MRI or PET scan), and evaluation of participant s veins that are used for drawing blood. If the participant is eligible for the study based on the screening evaluation, they will have a baseline evaluation prior to receiving the experimental treatment which may include additional laboratory or imaging tests. Participants will have a large IV catheter inserted into a vein to undergo a procedure called leukapheresis. Leukapheresis is the removal of the blood by a machine to collect specific white blood cells. The remaining blood is returned to the body. This procedure is needed to collect the cells that will be modified to target the cancer. The cells are grown in the lab and given back to the participant through an injection into the participant's tumor. It takes 11-15 days to grow the cells. While the cells are growing, the participant will be admitted to the hospital about one week before the cell infusion to receive 2 types of chemotherapy through an IV catheter over 5 days. The main purpose of the chemotherapy is to make the cells more effective in fighting the cancer tumors. The cells will be given 1-2 days after the last dose of chemotherapy. Within 24 hours after the cell infusion, participants will be given a cell growth factor called aldesleukin through an IV for up to 4 days. Aldesleukin is thought to help the cells live longer in the participant s body. Participants will recover in the hospital until they are well enough to go home, which is usually about 7-12 days after the cell infusion or last dose of aldesleukin. Participants will have a follow-up visit at approximately 40 days after the date of cell infusion. This visit will be to evaluate the safety of the cell therapy and the response of the cancer to the treatment which will include physical examination, lab tests, and imaging studies. If a participant has stable disease or their cancer has responded to the treatment, they will be seen again at 12 weeks post cell infusion, every 3 months x 3 visits, and then every 6 months x 5 years. If a participant s cancer progresses after this therapy, they will be return to their home doctor for further management. After receiving cell therapy, participants will be followed on a long-term gene therapy protocol. Participants will have blood drawn periodically to test if the cells have grown or changed. These blood tests will take place immediately before the cells, and then at 3, 6, and 12 months for the first year and possibly annually thereafter based on the results. These tests can be drawn locally and sent to the NIH. After a participant is off the study, they will be contacted by telephone or mailed questionnaire for a total of 15 years after cell therapy....

Research Team

Scott M Norberg, D.O.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

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]

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]

References

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

WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Rebalancing immune specificity and function in cancer by T-cell receptor gene therapy. [2021]

3. England pubmed.ncbi.nlm.nih.gov

T-cell receptor gene therapy for cancer: the progress to date and future objectives. [2019]

4. Germany 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. [2023]

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

Requirements for effective antitumor responses of TCR transduced T cells. [2019]

6. France pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. [2022]

7. England pubmed.ncbi.nlm.nih.gov

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

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

T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk. [2021]

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

Building safety into CAR-T therapy. [2023]

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

T-cell receptor gene therapy--ready to go viral? [2021]

11. England pubmed.ncbi.nlm.nih.gov

T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

TCR-T Immunotherapy: The Challenges and Solutions. [2022]

13. United States 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. [2008]