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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine the effect of a special preparation of cells, called tumor-infiltrating lymphocytes (TIL) stimulated with CD40L, when given with the drug nivolumab, for patients with EGFR, ALK, ROS1, or HER2-genomically altered lung cancer.

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.

What data supports the effectiveness of the treatment TIL + Nivolumab for lung cancer?

In a phase 1 trial, the combination of tumor-infiltrating lymphocyte (TIL) therapy and the drug nivolumab showed preliminary signs of effectiveness in patients with advanced non-small cell lung cancer, with some patients experiencing a reduction in tumor size and a few achieving complete responses lasting over a year. ^{1 2 3 4 5}

Is the combination of TIL therapy and Nivolumab safe for humans?

The combination of tumor-infiltrating lymphocyte therapy and the drug Nivolumab has been considered safe and tolerable in a phase I clinical trial for patients with advanced lung cancer. However, immune-related side effects, such as skin issues, are common with Nivolumab and similar drugs. ^{4 6 7 8 9}

How is the TIL + Nivolumab treatment different from other treatments for lung cancer?

The TIL + Nivolumab treatment is unique because it combines tumor-infiltrating lymphocytes (TILs), which are immune cells extracted and expanded from a patient's own tumor, with Nivolumab, an immune checkpoint inhibitor. This approach aims to enhance the body's immune response against cancer, especially in cases where patients have not responded to Nivolumab alone. ^{1 2 5 10 11}

Research Team

Ben C Creelan, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer. [2022]

2. England 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. [2022]

3. Poland 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. [2023]

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

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

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

Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. [2023]

7. Switzerland 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. [2023]

8. China 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. [2022]

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

Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. [2022]

10. England 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. [2022]

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

PD-1T TILs as a Predictive Biomarker for Clinical Benefit to PD-1 Blockade in Patients with Advanced NSCLC. [2023]