TIL + Nivolumab for Lung Cancer

Overseen By Ben Creelan

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: PD-1 inhibitors

Disqualifiers: Autoimmune disease, Rapidly progressing tumors, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination treatment for certain types of advanced lung cancer with specific genetic changes. The study examines how tumor-infiltrating lymphocytes (TIL), a special type of immune cell treatment, work alongside the drug nivolumab (Opdivo). Individuals with advanced non-small cell lung cancer and specific genetic alterations (EGFR, ALK, ROS1, or HER2) who have tried at least one other treatment might be suitable candidates. The goal is to determine if this combination can control the cancer more effectively. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not be on chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment, except for certain exceptions like low-dose oral hydrocortisone for adrenal insufficiency.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nivolumab is usually well-tolerated by patients with non-small-cell lung cancer (NSCLC). In studies, about 3.6% of patients experienced serious side effects when nivolumab was combined with chemotherapy, including infections like sepsis. Most other side effects were manageable.

For tumor-infiltrating lymphocytes (TIL), studies have shown promising results in various solid tumors, including lung cancer. Most side effects were temporary and related to immune system activation. Long-term safety data suggest no major concerns over extended periods.

Both treatments have been studied separately and appear to have manageable safety profiles. However, combining them in this trial might yield different results, so it's important to consider this when deciding to join. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for lung cancer, which typically involve chemotherapy, targeted therapies, or radiation, the combination of Nivolumab and Tumor-infiltrating Lymphocytes (TILs) offers a novel approach by harnessing the power of the immune system. Nivolumab is an immune checkpoint inhibitor that helps activate T-cells to attack cancer cells, while TILs are a form of personalized cell therapy using the patient's own immune cells to target the tumor. This dual approach aims to enhance the body's natural defenses against cancer, potentially leading to more effective and durable responses. Researchers are excited about this treatment because it represents a shift towards more personalized and potentially less toxic cancer therapies, offering hope for improved outcomes in lung cancer patients.

What evidence suggests that this trial's treatments could be effective for lung cancer?

This trial will evaluate the combination of tumor-infiltrating lymphocytes (TIL) therapy with nivolumab for treating lung cancer. Research has shown that TIL therapy can lead to lasting and significant improvements in non-small cell lung cancer (NSCLC). Nivolumab helps the immune system attack cancer cells more effectively. Early results suggest that combining these treatments can benefit patients with specific genetic changes, such as EGFR, ALK, ROS1, or HER2. Overall, this approach offers new hope for patients with difficult-to-treat lung cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Ben C Creelan, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with stage IV or recurrent NSCLC who have specific genetic alterations (EGFR, ALK, ROS1, HER2) and have progressed after at least one systemic therapy. They must have a tumor that can be biopsied for TIL harvest and adequate organ function. Those with certain heart conditions, uncontrolled illnesses, more than six prior NSCLC therapies, previous PD-1/PD-L1 inhibitor treatment for metastatic NSCLC or active infections are excluded.

Inclusion Criteria

I am fully active or can carry out light work.

My NSCLC worsened after treatment, including targeted therapy if applicable.

My brain metastases are stable or treated, and I don't need immediate brain-specific treatment.

Exclusion Criteria

You have received an organ from someone else in the past.

You have had a serious allergic reaction to beta-lactam antibiotics in the past.

My cancer is growing quickly, according to my doctor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab infusion every 3 weeks prior to lymphodepletion chemotherapy with cyclophosphamide/fludarabine, followed by TIL infusion and interleukin-2, then nivolumab infusion every 4 weeks up to 12 months

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Tumor-infiltrating Lymphocytes (TIL)

Trial Overview The trial tests the effectiveness of CD40L-stimulated TILs combined with nivolumab in patients with genetically altered lung cancer. It aims to see how well these specially prepared immune cells work when given alongside an established immunotherapy drug.

How Is the Trial Designed?

Group I: TIL+ Nivolumab Experimental Treatment 6 Interventions

Nivolumab infusion every 3 weeks prior to lymphodepletion chemotherapy with cyclophosphamide/fludarabine, TIL infusion and interleukin-2. Then nivolumab infusion every 4 weeks up to 12 months.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

In a phase I clinical trial, tumor-infiltrating lymphocyte therapy combined with nivolumab (an anti-PD-1 drug) was found to be safe and well-tolerated in patients with stage IV or recurrent non-small cell lung cancer.

The combination therapy showed preliminary signs of efficacy, suggesting it may be a promising treatment option for advanced lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-Infiltrating Lymphocytes Help Rein In NSCLC. [2021]

In a phase 1 trial involving 20 patients with advanced non-small cell lung cancer, adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) combined with nivolumab was found to be generally safe, meeting the safety criteria with a severe toxicity rate of ≤17%.

Of the 13 evaluable patients, 3 showed confirmed responses to the treatment, and 11 experienced a reduction in tumor burden, indicating that TIL therapy may be an effective new strategy for treating metastatic lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Creelan, BC., Wang, C., Teer, JK., et al.[2023]

PD-1T tumor-infiltrating T lymphocytes (TILs) were identified as a promising predictive biomarker for the effectiveness of PD-1 blockade in advanced non-small cell lung cancer (NSCLC), showing 77% sensitivity and 67% specificity at 6 months.

Patients with high levels of PD-1T TILs experienced significantly longer progression-free and overall survival, indicating that this biomarker can help identify patients who are likely to benefit from treatment, while also accurately identifying those who may not benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1T TILs as a Predictive Biomarker for Clinical Benefit to PD-1 Blockade in Patients with Advanced NSCLC. Hummelink, K., van der Noort, V., Muller, M., et al.[2023]

Over 40% of melanoma patients treated with anti-PD-1 therapy experience dermatologic immune-related adverse events (irAEs), but these are typically self-limiting and manageable, with common issues including rashes and itching.

Both anti-PD-1 and anti-PD-L1 antibodies show a similar dermatologic safety profile, and while these skin reactions are frequent, they rarely lead to severe complications or the need to stop treatment, highlighting the importance of early recognition and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Sibaud, V., Meyer, N., Lamant, L., et al.[2022]

TCF1+PD-1+ tumor-infiltrating lymphocytes (TILs) are associated with better responses to immune checkpoint inhibitor (ICI) therapy in non-small-cell lung cancer (NSCLC), as shown in a study involving 234 patients with RNA sequencing and 116 patients with immunohistochemistry.

A higher number of TCF1+PD-1+ TILs correlates with improved progression-free survival (PFS) and overall survival (OS) after ICI therapy, indicating their potential as a predictive biomarker for treatment outcomes in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCF1+PD-1+ tumour-infiltrating lymphocytes predict a favorable response and prolonged survival after immune checkpoint inhibitor therapy for non-small-cell lung cancer. Koh, J., Kim, S., Woo, YD., et al.[2022]

In a study of 137 non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery, those with medium to high levels of tumor-infiltrating lymphocytes (TIL+) had significantly better overall survival (OS) and disease-free survival (DFS) compared to those with low TIL levels (TIL-).

TIL+ status was identified as an independent prognostic factor for improved outcomes, while factors such as smoking and advanced clinical stage were associated with poorer prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The prognostic value of tumor-infiltrating lymphocytes in non-small cell lung cancer patients who received neoadjuvant chemotherapy followed by surgery. Hou, Z., Zhao, L., Zou, L., et al.[2023]

In a study of 109 advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), 50.5% experienced immune-related adverse events (irAEs), with baseline levels of CD8+ T lymphocytes identified as a significant predictor for these events.

Higher baseline CD8+ T lymphocyte levels not only correlated with an increased risk of irAEs but also indicated better clinical outcomes, with longer progression-free survival (PFS) and overall survival (OS) in patients who experienced irAEs compared to those with lower levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Positive Correlation of Peripheral CD8+ T Lymphocytes with Immune-Related Adverse Events and Combinational Prognostic Value in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors. Wu, K., Xia, B., Zhang, J., et al.[2023]

In a meta-analysis of 18 studies involving 5,649 patients with non-small cell lung cancer, first-line therapy using PD-1/PD-L1 inhibitors showed a significantly higher risk of treatment-related adverse events (trAEs) and immune-related adverse events (irAEs) compared to subsequent therapies, indicating a need for careful monitoring in initial treatments.

Despite the higher incidence of adverse events in first-line therapy, the types of trAEs and irAEs were largely similar across different therapy lines, suggesting that while the severity may differ, the overall spectrum of side effects remains consistent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis. Yang, Y., Pang, P., Xie, Z., et al.[2022]

In a study of 378 non-small cell lung cancer (NSCLC) patients, high levels of CD8+PD-L1+ tumor-infiltrating lymphocytes (TILs) were associated with a worse prognosis in patients not receiving immunotherapy, indicating an immunosuppressive tumor microenvironment.

However, in patients undergoing anti-PD-1 treatment, higher levels of CD8+PD-L1+ TILs correlated with better responses to therapy, suggesting that PD-1 pathway blockade can alleviate immunosuppression and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer. Zhang, L., Chen, Y., Wang, H., et al.[2022]

The TIL 3.0 method, which uses IL-2 combined with agonistic antibodies, significantly enhances the expansion of tumor-infiltrating lymphocytes (TIL) from non-small cell lung cancer (NSCLC) tumors, producing 5.3 times more TIL compared to the traditional TIL 1.0 method.

TIL 3.0 not only increases the quantity of CD8+ TIL but also maintains a diverse T-cell repertoire that closely resembles the original tumor's clonal hierarchy, suggesting a greater potential for effective adoptive cell transfer therapies in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes. Shah, P., Forget, MA., Frank, ML., et al.[2022]

In a study of 126 patients with EGFR-mutant non-small-cell lung cancer, 15% experienced severe immune-related adverse events (irAEs) when treated with sequential PD-(L)1 blockade followed by osimertinib, particularly within 3 months of PD-(L)1 treatment.

No severe irAEs were reported when osimertinib was administered before PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs, indicating that the severe toxicity is specifically associated with the sequence of PD-(L)1 followed by osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Schoenfeld, AJ., Arbour, KC., Rizvi, H., et al.[2023]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs002486.v1.p1

Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in ... - NCBI This project investigates why some non-small cell lung cancer (NSCLC) patients respond poorly to immunotherapy, specifically anti-PD1 treatments. We are ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03215810

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3. 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.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2405803325002006

Immune correlates and mechanisms of TIL therapy efficacy Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a transformative approach in cancer immunotherapy, particularly following the ...

5. astctjournal.org astctjournal.org/article/S2666-6367(24)00783-8/fulltext

Tumor-Infiltrating Lymphocyte Therapy: A New Frontier This trial indicated that TIL therapy could achieve durable and meaningful responses in NSCLC, including in the important subset of never-smoker lung cancer ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7738788/

Real-World Safety and Efficacy of Nivolumab in Advanced ... There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) ...

7. opdivohcp.com opdivohcp.com/efficacy/nsclc

Efficacy Data for Non-Small Cell Lung Cancer (NSCLC) - Opdivo Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%). OPDIVO and/or ...

8. opdivo.com opdivo.com/clinical-trial-results

Clinical Trial Results Select your cancer type above to see how OPDIVO, alone or in combination with other therapies, performed in clinical trials.

9. jto.org jto.org/article/S1556-0864(24)02355-4/fulltext

Long-Term Survival Outcomes With First-Line Nivolumab ... In patients with squamous NSCLC, median OS was 16.2 versus 8.2 months with nivolumab plus ipilimumab with or without chemotherapy versus ...

10. news.bms.com news.bms.com/news/details/2022/Landmark-Five-Year-Data-from-Phase-3-CheckMate--227-Trial-Demonstrate-Long-Term-Durable-Survival-Outcomes-with-Opdivonivolumab-Plus-Yervoy-ipilimumab-in-First-Line-Treatment-of-Patients-with-Metastatic-Non-Small-Cell-Lung-Cancer/default.aspx

Landmark Five-Year Data from Phase 3 CheckMate -227 ... Opdivo plus Yervoy nearly doubled overall survival rate at five years compared to chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC)