TIL Therapy for Biliary Tract Cancer

Recruiting at 1 trial location

Overseen By Josh Tobin

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Udai Kammula

Must not be taking: 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 (+/- 2 weeks)

59 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called Tumor Infiltrating Lymphocytes (TIL) to determine its effectiveness for certain biliary tract cancers, such as cholangiocarcinoma and gallbladder cancer, which are typically difficult to treat. The goal is to see if this approach can shrink tumors or slow their growth. Patients who have tried other treatments without success and have advanced, inoperable cancer might be suitable candidates. Participants should be physically able to undergo specific chemotherapy and immune-boosting treatments. 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. This suggests a possible need to pause certain treatments.

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

Research shows that Tumor Infiltrating Lymphocytes (TIL) therapy could effectively help the immune system fight cancer. Although specific safety information for TIL therapy in biliary tract cancer is not yet available, similar treatments have been studied and are usually well-tolerated.

In past studies, TIL therapy proved safe for patients with other types of cancer. However, this is a Phase 2 study, which means the researchers are still assessing the treatment's safety. Participants might experience some side effects, so discussing these with the clinical team is important.

Overall, current evidence suggests TIL therapy has potential, but more research is needed to fully understand its safety in biliary tract cancer. ^{1 2 3 4 5}

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

Unlike the standard treatments for biliary tract cancer, which often include chemotherapy and targeted therapies, Tumor Infiltrating Lymphocytes (TIL) therapy takes a more personalized approach by using a patient's own immune cells to fight the cancer. Researchers are excited about TIL therapy because it directly targets and attacks cancer cells, potentially offering a more effective and specific treatment. This therapy involves infusing a large number of these activated immune cells back into the patient after a preparative regimen, which could lead to a stronger immune response compared to standard treatments. Additionally, the use of Aldesleukin to boost the immune cells' activity further distinguishes this therapy, offering hope for improved outcomes in patients with advanced biliary tract cancer.

What evidence suggests that Tumor Infiltrating Lymphocytes (TIL) might be an effective treatment for biliary tract cancer?

Research shows that Tumor Infiltrating Lymphocytes (TILs) can be a strong weapon against cancer. TILs are immune cells taken from a patient's tumor, grown in a lab, and then returned to the patient's body to combat the cancer. Studies have found that TILs hold promise for patients with hard-to-treat cancers. For example, they effectively killed cancer cells in lab tests. Early results also suggest that TIL therapy can significantly shrink tumors in some patients. This trial will evaluate TIL therapy for biliary tract cancers, which currently have few treatment options, offering hope for improved outcomes. ^{1 2 6 7 8}

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 advanced, recurrent, or metastatic biliary tract cancers who have not responded to standard treatments. They must be able to handle specific chemotherapy and high-dose aldesleukin, sign informed consent, have an ECOG performance status of 0 or 1 (fully active or restricted in physically strenuous activity but ambulatory), and agree to birth control measures. Those with small, stable brain metastases may qualify.

Inclusion Criteria

Able to understand and sign the Informed Consent Document

I agree to use birth control during and up to four months after the study.

I am enrolled in HCC 17-220 and have TIL cultures ready for therapy.

Exclusion Criteria

You have had a serious allergic reaction to any of the medications used in this study in the past.

You are not currently taking any other experimental drugs or treatments.

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

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 Tumor Infiltrating Lymphocytes (TIL) for growth and expansion.

Variable

Treatment

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

6 weeks (+/- 2 weeks)

Multiple visits for chemotherapy and TIL infusion

Follow-up

Participants are monitored for safety, tumor response, and immunologic parameters after treatment.

Up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Tumor Infiltrating Lymphocytes (TIL)

Trial Overview The study tests the effectiveness of Tumor Infiltrating Lymphocytes (TIL) therapy combined with a non-myeloablative lymphodepleting regimen followed by high-dose aldesleukin in patients with biliary tract cancer. It's a Phase 2 trial aiming to see if this approach can shrink tumors in those who haven't had success with other treatments.

How Is the Trial Designed?

Group I: Tumor Infiltrating Lymphocytes (TIL) Experimental Treatment 1 Intervention

Patients with locally advanced, recurrent, or metastatic biliary tract cancers will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide, followed by infusion of up to 2x10\^11 lymphocytes infused intravenously through a central vein catheter and Aldesleukin, 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

The combination of panitumumab with gemcitabine and irinotecan showed promising efficacy in treating advanced cholangiocarcinoma, achieving a 5-month progression-free survival (PFS) rate of 69% and a median PFS of 9.7 months among 35 patients.

The treatment was generally well-tolerated, with a disease-control rate of 74% and manageable side effects, indicating that this regimen could be a viable option for patients with unresectable or metastatic biliary tract cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma. Sohal, DP., Mykulowycz, K., Uehara, T., et al.[2022]

In a study of 30 patients with previously treated HER2-positive metastatic biliary tract cancer, the combination of tucatinib and trastuzumab showed a confirmed objective response rate of 46.7%, indicating significant antitumor activity.

The treatment was generally well tolerated, with common side effects including fever and diarrhea, but no deaths were attributed to treatment-related adverse events, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. Nakamura, Y., Mizuno, N., Sunakawa, Y., et al.[2023]

Immunotherapy shows promise as a novel treatment for biliary tract cancers (BTC), which are typically resistant to chemotherapy, with initial studies indicating potential benefits from various approaches like targeted vaccines and immune checkpoint inhibitors.

Ongoing clinical trials are crucial to confirm the efficacy of immunotherapy in BTC and to identify which patients may benefit most, as well as to explore combination therapies that could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future. Blair, AB., Murphy, A.[2019]

In a study involving 39 patients with HER2-positive metastatic biliary tract cancer, the combination of pertuzumab and trastuzumab resulted in a promising objective response rate of 23%, indicating potential efficacy for this treatment in a challenging cancer type.

The treatment was generally well tolerated, with 46% of patients experiencing grade 3-4 adverse events, but no treatment-related serious adverse events or deaths were reported, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Javle, M., Borad, MJ., Azad, NS., et al.[2021]

Cholangiocarcinoma tumors show a decrease in cytotoxic T cells and an increase in regulatory T cells, indicating an immunosuppressive tumor microenvironment that hinders effective immune responses.

Targeting immune checkpoint molecules like PD1, CTLA4, and GITR can enhance the function of tumor-infiltrating T cells, suggesting these targets could be promising for immunotherapy in cholangiocarcinoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. Zhou, G., Sprengers, D., Mancham, S., et al.[2020]

In a study of 154 patients with biliary tract cancers, a high preoperative neutrophil-to-lymphocyte ratio (NLR) was linked to shorter overall survival (OS) and recurrence-free survival (RFS), indicating it may serve as a negative prognostic factor.

Conversely, a high level of CD8+ tumor-infiltrating lymphocytes (TILs) was associated with longer OS and RFS, suggesting that these immune cells may play a protective role against cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative Neutrophil-to-lymphocyte Ratio Predicts Tumor-infiltrating CD8+ T Cells in Biliary Tract Cancer. Tanaka, R., Kimura, K., Eguchi, S., et al.[2020]

The combination therapy of allogeneic natural killer (NK) cells and pembrolizumab was found to be safe, with no severe adverse events directly related to the treatment in phase 1, and only 47.1% of patients in phase 2a experiencing severe adverse events.

This treatment showed promising antitumor activity, achieving an overall response rate of 17.4% in the full analysis set and 50.0% in the per-protocol set, indicating improved efficacy compared to pembrolizumab alone in patients with advanced biliary tract cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Allogeneic Natural Killer Cells in Combination with Pembrolizumab in Patients with Chemotherapy-Refractory Biliary Tract Cancer: A Multicenter Open-Label Phase 1/2a Trial. Leem, G., Jang, SI., Cho, JH., et al.[2022]

In a study of 33 patients with advanced biliary tract cancers, those treated with immune checkpoint inhibitors showed significantly better overall survival (10+ months) and progression-free survival (10+ months) compared to those receiving chemotherapy (2 months OS and 4 months PFS).

The effectiveness of immunotherapy was particularly pronounced in patients with high PD-L1 expression (>10%), while the safety profile was comparable to chemotherapy, indicating that immune checkpoint inhibitors can be a viable treatment option for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficiency and safety of immune checkpoint inhibitors for advanced biliary tract cancers based on gene profiles: A retrospectively controlled study. Yao, GL., Fan, YG.[2022]

Biliary tract cancers (BTC) have poor long-term survival rates, and while systemic chemotherapy and targeted therapies have had limited success, immunotherapy shows promise as a potential treatment option.

Current research includes various immunotherapy approaches such as autologous cell transfer and immune checkpoint inhibitors, with ongoing studies aimed at improving treatment outcomes for BTC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Progress in Immunotherapy for the Treatment of Biliary Cancers. Pauff, JM., Goff, LW.[2018]

In a study of 130 patients with biliary tract cancer, a high Immunoscore, based on the presence of specific immune cells, was associated with significantly better overall survival (60.8 months vs. 26.4 months) and recurrence-free survival compared to a low Immunoscore.

The high Immunoscore was identified as an independent prognostic factor for both overall survival and recurrence-free survival, indicating its potential as a valuable marker in assessing patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes and macrophages as a significant prognostic factor in biliary tract cancer. Tanaka, R., Eguchi, S., Kimura, K., et al.[2023]

In a study of 35 liver cancer specimens, both hepatocellular and cholangiolar carcinomas showed significant infiltration of tumor-infiltrating lymphocytes (TIL), particularly CD4+ T cells at the tumor/liver interface and CD8+ T cells within the tumor itself.

The presence of these lymphocytes suggests they may play distinct roles in the immune response against liver tumors, although their distribution and quantity did not differ significantly between the two types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. Kasper, HU., Drebber, U., Stippel, DL., et al.[2021]

In a study of 83 patients with extrahepatic bile duct (EHBD) cancer, a higher ratio of PD-1(+) to CD8(+) tumor-infiltrating lymphocytes (TILs) was linked to significantly poorer overall survival, relapse-free survival, and distant metastasis-free survival, indicating its potential as a critical prognostic factor.

The findings suggest that targeting the immune checkpoint pathways, particularly in patients with a high PD-1(+)/CD8(+) TIL ratio, could enhance treatment outcomes when combined with conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High ratio of programmed cell death protein 1 (PD-1)(+)/CD8(+) tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy. Lim, YJ., Koh, J., Kim, K., et al.[2018]

In a study of 49 patients with advanced biliary tract cancer, the triple combination therapy of local-regional treatment, PD-1 inhibitors, and lenvatinib resulted in a longer median progression-free survival (7.9 months) compared to lenvatinib plus toripalimab alone (5.6 months).

The overall response rate for the triple combination therapy was 32%, indicating promising efficacy, and importantly, this treatment did not lead to increased specific toxicities, making it a potentially safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local-regional therapy combined with toripalimab and lenvatinib in patients with advanced biliary tract cancer. Wang, Y., Xun, Z., Yang, X., et al.[2023]

In a phase II trial involving 32 patients with advanced biliary tract cancer, the combination of nivolumab with gemcitabine and cisplatin resulted in a 55.6% objective response rate, indicating promising efficacy for this treatment approach.

The treatment was generally safe, with manageable side effects; however, the most common severe adverse events included thrombocytopenia (56%) and neutropenia (22%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study. Feng, K., Liu, Y., Zhao, Y., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03801083

Study Details | NCT03801083 | Adoptive Transfer of Tumor ... This is a Phase 2 study to evaluate the efficacy, using objective response rate, of a non-myeloablative lymphodepleting preparative regimen followed by ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8988317/

The role of tumor-infiltrating lymphocytes in ... Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy.

3. academic.oup.com academic.oup.com/jimmunol/advance-article/doi/10.1093/jimmun/vkaf242/8255914

Development of a murine tumor-infiltrating lymphocyte therapy ... Tumor Ag TILs displayed superior tumor lysis in vitro compared to CD3 TILs. While both TIL products engrafted in vivo, Tumor Ag TILs showed ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11393248/

Recent clinical researches and technological development in ... TILs, which are extracted from a patient's tumor, expanded in a laboratory, and reinfused to fight cancer, have shown promising results even in ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/30/20/4635/748799/Artificial-Intelligence-Powered-Spatial-Analysis

Artificial Intelligence-Powered Spatial Analysis of Tumor ... Our results show that IP classification by AI-powered spatial analysis of TIL may be employed for the prediction of efficacy in patients with advanced BTC ...

6. withpower.com withpower.com/trial/phase-3-biliary-tract-neoplasms-1-2019-eca4b

TIL Therapy for Biliary Tract Cancer There is no specific safety data available for TIL therapy in biliary tract cancer, but similar immune therapies have been studied and found to be generally ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0753332224009648

Tumor-infiltrating T lymphocytes: A promising ... Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01174121

NCT01174121 | Immunotherapy Using Tumor Infiltrating ... We propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer therapy in combination with pembrolizumab, administered either prior to ...