TIL Therapy for Advanced Cancer

Overseen By Josh Tobin

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Udai Kammula

Must not be taking: Systemic steroids, Anti-infectives

Disqualifiers: Pregnancy, Immunodeficiency, Infections, 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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for advanced cancers using Tumor Infiltrating Lymphocytes (TIL). TIL therapy uses a patient's own immune cells to combat cancers that have spread or recurred, such as gastric, colorectal, and pancreatic cancers. It targets patients whose previous cancer treatments have failed and includes a special preparation process to enhance the immune response. This trial suits those with specific types of advanced cancer who have not succeeded with other treatments and face frequent challenges in daily life due to their condition. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that more than four weeks must have passed since any prior systemic therapy before starting the preparative regimen. It's best to discuss your current medications with the trial team to get specific guidance.

Is there any evidence suggesting that Tumor Infiltrating Lymphocytes (TIL) therapy is likely to be safe for humans?

Research has shown that tumor-infiltrating lymphocytes (TIL) therapy has been studied for its safety in treating cancer. One study found that about 3.2% of patients experienced serious side effects leading to death within 30 days after therapy. Despite this, the treatment's side effects are generally similar to those of other less intense therapies, which often result from the preparation process.

The FDA has approved this treatment for melanoma, indicating an acceptable safety profile for this condition. This approval suggests the treatment is generally well-tolerated, although individual experiences can vary. Potential participants should consult their doctors to understand the specific risks and benefits for their situation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for advanced cancer?

Unlike the standard cancer treatments, which often involve chemotherapy or radiation targeting cancer cells broadly, Tumor Infiltrating Lymphocytes (TIL) therapy is unique because it uses the patient's own immune cells to target and destroy cancer cells. This personalized approach harnesses TILs, which are naturally occurring immune cells found within tumors, to enhance their cancer-fighting ability. Researchers are excited about TIL therapy because it has the potential to be more effective against tumors that are resistant to traditional treatments, offering hope for patients with advanced cancers. Additionally, this therapy targets cancers with specific genetic features, such as deficient mismatch repair and microsatellite instability, making it a promising option for personalized cancer treatment.

What evidence suggests that TIL therapy might be an effective treatment for advanced cancer?

Research has shown that Tumor Infiltrating Lymphocytes (TIL) therapy, which participants in this trial will receive, holds promise for treating some advanced cancers. Studies have found that TIL therapy can significantly extend the time patients with advanced melanoma live without their cancer worsening, suggesting potential effectiveness for other cancers as well. Long-term studies indicate that TIL treatments, such as lifileucel, provide lasting benefits without major long-term safety issues. These positive results support the use of TIL therapy for cancers that are difficult to treat with standard methods. The therapy uses the body's own immune cells to fight cancer, which may explain its effectiveness. ^{1 6 7 8 9}

Who Is on the Research Team?

Udai S Kammula, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with certain advanced solid cancers, like pancreatic or colorectal cancer, who've tried all standard treatments. They must have a good performance status and life expectancy over three months. Women of childbearing age need a negative pregnancy test and agree to birth control.

Inclusion Criteria

I am willing to use birth control during the trial.

Able to understand and sign the Informed Consent Document

It's been over 4 weeks since my last systemic therapy, and any side effects are under control.

Exclusion Criteria

Patients who are receiving any other investigational agents

I am pregnant or breastfeeding.

I currently have an infection that affects my whole body.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Preparation

Patients undergo resection or biopsy of tumor to obtain TIL, which are then grown and expanded for the trial.

Variable

Treatment

Patients receive a lymphocyte depleting preparative regimen followed by infusion of TIL and high-dose aldesleukin.

6 weeks

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including tumor evaluation and toxicity assessment.

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Tumor Infiltrating Lymphocytes (TIL)

Trial Overview The study tests Tumor Infiltrating Lymphocytes (TIL) therapy combined with Fludarabine and Cyclophosphamide in patients with specific advanced cancers. It's checking how well this approach works after patients have had no success with conventional therapies.

How Is the Trial Designed?

Group I: Tumor Infiltrating Lymphocytes (TIL) Experimental Treatment 2 Interventions

Patients with locally advanced, recurrent, or metastatic gastric/esophagogastric, colorectal, pancreatic, sarcoma, mesothelioma, neuroendocrine, cutaneous/anal squamous cell, Merkel cell, cancers refractory to systemic therapy, and those with deficient mismatch repair and/or microsatellite instability cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes infused through a central vein catheter and administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to a maximum of 6 doses.

Tumor Infiltrating Lymphocytes (TIL) is already approved in United States for the following indications:

Approved in United States as Lifileucel (Amtagvi) for:

• Advanced melanoma that has worsened after treatment with certain immunotherapy drugs or targeted therapies

Who Is Running the Clinical Trial?

Udai Kammula

Lead Sponsor

Trials

3

Recruited

350+

Published Research Related to This Trial

A new method for isolating tumor-infiltrating lymphocytes (TIL) that express specific dysfunction markers (CD39, PD-1, and TIGIT) has been developed, allowing for efficient identification of neoantigen-reactive T-cell receptors (TCRs) from resected tumors, which is crucial for creating targeted cancer therapies.

Despite the initial success in isolating TIL with potential neoantigen reactivity, most expanded TIL populations showed functional impairment, indicating that while the isolation method is effective, the in vitro expansion process may hinder the TIL's ability to recognize and attack tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests. Chatani, PD., Lowery, FJ., Parikh, NB., et al.[2023]

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has shown promising results in causing tumor regression in various cancers, including melanoma and cervical squamous cell carcinoma, by utilizing the patient's own immune cells.

Recent advancements in T cell research and technology have improved the effectiveness of TIL ACT, making it a significant option in the landscape of cancer therapies, with ongoing clinical development focusing on optimizing patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell Therapy With TILs: Training and Taming T Cells to Fight Cancer. Kumar, A., Watkins, R., Vilgelm, AE.[2021]

In a study of 372 patients with advanced breast cancer, high concentrations of tumor-infiltrating lymphocytes (TILs) were associated with a better response to primary systemic therapy (PST), particularly in triple-negative and HER2-enriched subtypes.

High TIL levels correlated with improved disease-free survival (DFS) and overall survival (OS) in triple-negative and HER2-enriched breast cancers, indicating that TILs could serve as a valuable biomarker for treatment outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes in Patients with Advanced Breast Cancer Treated with Primary Systemic Therapy. Agarwal, G., Vishvak Chanthar, KMM., Katiyar, S., et al.[2023]

In the NeoALTTO trial involving 455 women with HER2-positive early breast cancer, higher levels of tumor-infiltrating lymphocytes (TILs) were linked to better outcomes, with a significant association between TIL levels above 5% and increased rates of pathological complete response (pCR).

Every 1% increase in TILs correlated with a 3% decrease in the rate of events during a median follow-up of approximately 3.77 years, indicating that TILs serve as a strong independent prognostic marker for event-free survival (EFS) in patients receiving neoadjuvant anti-HER2 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. Salgado, R., Denkert, C., Campbell, C., et al.[2022]

The study involved 196 patients from whom tumor-infiltrating lymphocytes (TILs) were safely harvested from 242 lesions, showing no mortality and minimal morbidity during the process.

Prior treatment with checkpoint inhibitors like ipilimumab was associated with higher TIL expansion, while those treated with anti-PD1 therapy had lower expansion, suggesting that previous immunotherapy may affect the effectiveness of TIL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue Harvesting for Adoptive Tumor Infiltrating Lymphocyte Therapy in Metastatic Melanoma. Zippel, D., Friedman-Eldar, O., Rayman, S., et al.[2019]

In a study involving 652 patients with HER2-positive metastatic breast cancer, low levels of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) were found to predict a greater benefit from trastuzumab (an antibody-based therapy) compared to lapatinib (a small molecule therapy).

Despite 35% of patients having high TIL counts, these did not show significant prognostic or predictive effects, indicating that the presence of CD8+ TILs may not always correlate with better outcomes in HER2-positive breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Cytotoxic Tumor-Infiltrating Lymphocytes in Predicting Outcomes in Metastatic HER2-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. Liu, S., Chen, B., Burugu, S., et al.[2022]

Tumor-infiltrating lymphocyte (TIL) therapy has shown promise in treating advanced solid cancers, with the potential for complete remission, and is now at a stage for formal clinical approval after extensive research and clinical trials.

To effectively implement TIL therapy in clinical practice, it is crucial to establish optimal protocols for cancer tissue sampling and manufacturing, as well as to expand its therapeutic indications and conduct further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocyte therapy: Clinical aspects and future developments in this breakthrough cancer treatment. Lee, H., Kim, K., Chung, J., et al.[2023]

The pilot clinical trial demonstrated that coadministering vemurafenib with tumor-infiltrating lymphocytes (TILs) for treating metastatic melanoma was safe and well tolerated, with a safety profile similar to that of either treatment alone.

Out of 11 patients, 64% showed an objective clinical response, and 18% achieved a complete response lasting up to 3 years, indicating promising efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma. Deniger, DC., Kwong, ML., Pasetto, A., et al.[2021]

High levels of tumor-infiltrating lymphocytes (TILs) in breast cancer are associated with better responses to neoadjuvant chemotherapy, indicating their potential role in treatment planning.

In particular, triple-negative and HER2-positive breast cancers with elevated TIL levels show improved survival rates, suggesting that TILs could serve as a valuable prognostic biomarker in routine histopathological assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Standardized determination of tumor-infiltrating lymphocytes in breast cancer : A prognostic marker for histological diagnosis]. Denkert, C., Loibl, S., Budczies, J., et al.[2022]

A retrospective analysis of 21 patients with advanced cutaneous melanoma showed that nonselected autologous tumor-infiltrating lymphocytes (TILs) resulted in a high overall response rate of 67% and a complete response rate of 19%, indicating significant efficacy even in patients who had previously undergone PD-1 inhibition.

The treatment was found to be safe, with no treatment-related deaths and a median overall survival of 21.3 months, suggesting that TIL therapy could be a promising option for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical feasibility and treatment outcomes with nonselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Pillai, M., Jiang, Y., Lorigan, PC., et al.[2022]

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]

In a Phase 2 trial involving 153 patients with advanced melanoma who had previously progressed on immune checkpoint inhibitors, lifileucel showed an objective response rate (ORR) of 31.4%, indicating its potential effectiveness in this challenging patient population.

The treatment demonstrated durable responses, with 41.7% of patients maintaining their response for at least 18 months, and a favorable safety profile, although common severe side effects included thrombocytopenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. Chesney, J., Lewis, KD., Kluger, H., et al.[2023]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00765

Long-Term Efficacy and Safety of Lifileucel Tumor ... This 5-year analysis demonstrated long-term benefit and meaningful OS with one-time lifileucel therapy, with no additional long-term safety concerns.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8376325/

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in ... Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0147027225000790

Current perspectives on Lifileucel tumor-infiltrating ... Lifileucel is a notable progress among the potential TIL treatments under development, exhibiting exceptional effectiveness in certain cancer types.,. This ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06481592

NCT06481592 | A Study of Lifileucel (Tumor-infiltrating ... The purpose of this study is to investigate the efficacy and safety of the lifileucel regimen in participants with previously treated endometrial cancer.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2210233

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in ... In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40454684/

Long-term Efficacy and Safety of Lifileucel Tumor ... Median overall survival (OS) was 13.9 months, with 5-year OS of 19.7%. Adverse events were consistent with nonmyeloablative lymphodepletion and ...

7. cancer.gov cancer.gov/news-events/cancer-currents-blog/2024/fda-amtagvi-til-therapy-melanoma

Lifileucel First Cellular Therapy Approved for Cancer - NCI FDA has approved lifileucel (Amtagvi), the first cancer treatment that uses immune cells called tumor-infiltrating lymphocytes, or TILs.

8. jitc.bmj.com jitc.bmj.com/content/10/12/e005755

Efficacy and safety of lifileucel, a one-time autologous ... Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT06538012

Study Details | NCT06538012 | TIL Therapy Combined ... This Phase I/II study evaluates the safety and efficacy of autologous tumor-infiltrating lymphocytes (TIL) therapy combined with Pembrolizumab (Keytruda) ...