Immunotherapy with TIL for Cancer

Recruiting at 1 trial location

Overseen By NCI/Surgery Branch Recruitment Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Steroids, Investigational agents

Disqualifiers: Pregnancy, Infections, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

332 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it mentions that patients must have completed any prior systemic therapy at the time of enrollment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Young TIL for cancer?

Research shows that tumor-infiltrating lymphocytes (TILs), like those used in Young TIL treatment, have been effective in causing the regression of metastatic melanoma, a type of skin cancer, especially when combined with interleukin-2 (a protein that boosts the immune system). This suggests that TILs can be powerful in fighting tumors with relatively few side effects since they are derived from the patient's own body. ^{1 2 3 4 5}

Is immunotherapy with tumor-infiltrating lymphocytes (TIL) generally safe for humans?

In studies of TIL therapy for advanced melanoma, no serious adverse effects were reported, suggesting it is generally safe. However, patients often receive interleukin-2 (IL-2) alongside TIL, which can have its own side effects, so monitoring is important. ^{5 6 7 8 9}

How is the Young TIL treatment different from other cancer treatments?

Young TIL treatment is unique because it uses the patient's own immune cells, specifically tumor-infiltrating lymphocytes, which are isolated, expanded, and then reintroduced to target and kill cancer cells. This approach minimizes adverse reactions since the cells are not genetically modified and are derived from the patient's body, offering a personalized and potentially more effective treatment for solid tumors. ^{1 3 4 10 11}

What is the purpose of this trial?

Background: The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. Researchers want to know if TIL shrink s tumors in people with digestive tract, urothelial, breast, or ovarian/endometrial cancers. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells. Objective: The purpose of this study is to see if these specifically selected tumor fighting cells can cause digestive tract, urothelial, breast, or ovarian/endometrial tumors to shrink and to see if this treatment is safe. Eligibility: - Adults age 18-72 with upper or lower gastrointestinal, hepatobiliary, genitourinary, breast, ovarian/endometrial cancer, or glioblastoma refractory to standard chemotherapy. Design: Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed. Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product. Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. (Leukapheresis is a common procedure, which removes only the white blood cells from the patient.) Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Research Team

Steven A Rosenberg, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-72 with certain types of metastatic cancer (digestive tract, breast, ovarian/endometrial, etc.) who haven't responded to standard treatments. Participants must not have HIV or hepatitis, agree to birth control and testing if applicable, and be in relatively good health otherwise.

Inclusion Criteria

You do not have HIV, hepatitis B, or hepatitis C in your blood.

Certain blood and chemistry test results must meet specific requirements.

My cancer is metastatic and falls into one of the specified categories.

Exclusion Criteria

I do not have any active infections, bleeding disorders, or serious illnesses.

My lung function (FEV1) is 50% or less.

I am on steroids, but only because my brain cancer requires it.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Work up stage

Patients undergo history and physical examination, scans, x-rays, lab tests, and other tests as needed

1-2 weeks

1-2 visits (in-person)

Surgery

Patients undergo surgery to remove a tumor for TIL product growth

1 week

1 visit (in-person)

Leukapheresis

Patients may undergo leukapheresis to obtain additional white blood cells

1 day

1 visit (in-person)

Treatment

Patients receive conditioning chemotherapy, TIL cells, and aldesleukin, and stay in the hospital for about 4 weeks

4 weeks

Inpatient stay

Follow-up

Patients return to the clinic for physical exams, review of side effects, lab tests, and scans every 1-3 months for the first year, then every 6 months to 1 year

Up to 2 years

Multiple visits (in-person)

Treatment Details

Interventions

• Young TIL

Trial Overview The trial is testing a therapy where white blood cells from the patient's tumor are grown in large numbers and reinfused into them. The study aims to see if these Tumor Infiltrating Lymphocytes (TIL) can shrink tumors effectively and safely.

Participant Groups

Group I: 5/Unselected TIL + Pembro Prior to Cells Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeks following cell infusion

Group II: 4/Unselected TIL + Pembro at POD Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab within 4 weeks of progressive disease for up to 8 doses every 3 weeks

Group III: 3/Unselected TIL + Pembro Prior to Cells Experimental Treatment 5 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeks following cell infusion

Group IV: 2/Unselected TIL (CLOSED) Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young unselected TIL + high-dose aldesleukin (CLOSED)

Group V: 1/CD8+ Enriched TIL (CLOSED) Experimental Treatment 4 Interventions

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + young CD8+ enriched TIL + high-dose aldesleukin (CLOSED)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Tumor-infiltrating lymphocytes (TILs) are a promising treatment for solid tumors, as they are derived from the patient's own body and have fewer adverse reactions compared to genetically modified therapies.

Despite their potential, the effectiveness of TIL therapy is currently limited by challenges in the immune microenvironment and antigen mutations, which the article reviews in terms of enhancing their therapeutic impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. Lin, B., Du, L., Li, H., et al.[2021]

In a study using both immune-deficient nude mice and normal A/J mice, the use of anti-PD-1 and anti-PD-L1 antibodies effectively suppressed tumor growth in A/J mice, highlighting the critical role of T lymphocytes in the antitumor immune response.

The research found that increased infiltration of activated CD8+ tumor-infiltrating lymphocytes (TILs) was associated with smaller tumor sizes, suggesting that enhancing CD8+ TIL infiltration could be a promising strategy for treating neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade. Inoue, S., Takeuchi, Y., Horiuchi, Y., et al.[2023]

A simplified method for generating CD8+ enriched 'young' tumor-infiltrating lymphocytes (TIL) was successfully established, allowing for treatment of 33 melanoma patients, with 58% showing an objective response after therapy.

The study demonstrated that this approach could lead to significant clinical responses, including complete regression in some patients, suggesting it could be a viable option for advanced melanoma treatment without the need for individualized tumor-reactivity screening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Dudley, ME., Gross, CA., Langhan, MM., et al.[2021]

In a study of 38 patients with anal squamous cell carcinoma, high levels of CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs) were associated with better survival rates, indicating their potential as positive prognostic factors.

Conversely, high numbers of granzyme B+ cytotoxic TILs were linked to poorer outcomes, suggesting that these cells may be associated with therapy-resistant tumor clones, while regulatory T cells (Treg) did not show any significant prognostic impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Grabenbauer, GG., Lahmer, G., Distel, L., et al.[2020]

In a study involving 55 patients with various cancers, including melanoma, renal cell carcinoma, and colorectal cancer, only one patient showed an objective tumor response, indicating limited efficacy of tumor-infiltrating lymphocytes (TIL) as a treatment.

Patients receiving a higher dose of TIL (mean = 54.4 x 10^9) had a median survival of 11.8 months, suggesting a potential dose/benefit relationship, although overall response rates were not encouraging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer. Dillman, R., Schiltz, P., DePriest, C., et al.[2006]

Immunotherapy using tumor-infiltrating lymphocytes (TIL) activated with interleukin 2 (IL2) has shown promise in treating metastatic melanoma and renal cell carcinoma, with some patients experiencing complete or partial responses.

Despite the optimism surrounding TIL therapy, the current understanding of its antitumor mechanisms and the effects of systemic administration is still limited, highlighting the need for further clinical trials and research to optimize this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer therapy with tumor-infiltrating lymphocytes: evaluation of potential and limitations. Whiteside, TL.[2004]

Adoptive cell therapy using autologous tumor infiltrating lymphocytes (TIL) has shown promising results, with objective response rates of up to 52% in patients with advanced metastatic melanoma.

The treatment involves activating and expanding TILs outside the body before re-infusing them into the patient, followed by administration of Interleukin-2 (IL-2) to enhance the immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma. Considine, B., Hurwitz, ME.[2023]

Autologous tumor-infiltrating lymphocyte (TIL) therapy has shown strong and consistent clinical responses in metastatic melanoma patients across various clinical trials, indicating its potential as a significant treatment option even alongside newer therapies.

The review discusses important aspects of TIL therapy, including the use of lymphodepleting regimens and interleukin-2 (IL-2), highlighting both the efficacy and associated toxicity, as well as future strategies for improving TIL production and application in other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. Rohaan, MW., van den Berg, JH., Kvistborg, P., et al.[2019]

In a study of 10 patients with advanced melanoma treated with autologous tumor-infiltrating lymphocytes (TILs) and interleukin-2 (IL-2), no serious adverse effects were reported, indicating a favorable safety profile for this immunotherapy approach.

Among the patients, there were instances of complete and partial remission, with one patient surviving for 9 years post-treatment, suggesting potential long-term benefits; however, the presence of certain T cell types was associated with shorter overall survival, highlighting the need for further research into optimizing treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients. Saint-Jean, M., Knol, AC., Volteau, C., et al.[2021]

Tumor infiltrating lymphocytes (TIL) are becoming important in immunotherapy, and their effectiveness can be enhanced through various augmentation methods, both in vitro and in vivo.

The article discusses a specific technique called cyclophosphamide immunopriming, which is used to enhance TILs before they are applied in therapeutic protocols, potentially improving their ability to fight tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunopriming of tumor infiltrating lymphocytes with neoadjuvant cyclophosphamide. Guinan, P., Shaw, M., Rubenstein, M.[2019]

Tumor-infiltrating lymphocytes (TIL) expanded from tumors treated with a collagen matrix and recombinant human IL-6 (rIL-6) showed significantly enhanced antitumor efficacy compared to TIL from other treatment conditions in five separate experiments.

This study suggests that increasing local concentrations of cytokines like rIL-6 at tumor sites can improve the potency of TIL, potentially leading to more effective cancer therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of interleukin-6 to generate tumor-infiltrating lymphocytes with enhanced in vivo antitumor activity. Marcus, SG., Perry-Lalley, D., Mulé, JJ., et al.[2019]

References

1. France pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. [2021]

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

CD69 on Tumor-Infiltrating Cells Correlates With Neuroblastoma Suppression by Simultaneous PD-1 and PD-L1 Blockade. [2023]

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

CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. [2021]

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

Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. [2020]

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

Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer. [2006]

6. Greece pubmed.ncbi.nlm.nih.gov

Cancer therapy with tumor-infiltrating lymphocytes: evaluation of potential and limitations. [2004]

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

Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. [2019]

9. Egypt pubmed.ncbi.nlm.nih.gov

Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Immunopriming of tumor infiltrating lymphocytes with neoadjuvant cyclophosphamide. [2019]

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

The use of interleukin-6 to generate tumor-infiltrating lymphocytes with enhanced in vivo antitumor activity. [2019]