C-TIL051 + Anti-PD1 Therapy for Lung Cancer

Recruiting at 4 trial locations

Overseen By Shari Pearson

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AbelZeta, Inc.

Must be taking: Anti-PD1

Must not be taking: Immunosuppressives, Live vaccines

Disqualifiers: CNS metastases, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this Phase 1 clinical study is test tumor infiltrating lymphocytes (known as C-TIL051) with NKTR-255 and anti-PD1 therapy for subjects with refractory non-small cell lung cancer. The purpose of this study is to: 1. Test the safety and ability for subjects to tolerate the TIL therapy 2. Measure to see how the NSCLC responds to the TIL therapy Participants will be asked to: * Provide a tumor sample prior to the start of any treatment which will be used to make the C-TIL051. * Receive standard of care treatment until their lung cancer no longer responds * When necessary, the C-TIL051 will be manufactured by the sponsor and sent back to the site * Subject will then receive chemotherapy (called lymphodepletion) for 3 days followed by 2 days of rest * C-TIL051 will then be infused on day 0 followed by NKTR-255 (IL-15) about 12 to 24 hours later * Pembrolizumab will be administered every 3 weeks for up to 2 years NKTR-255 is a novel polymer-conjugated human IL-15 receptor agonist molecule designed to increase the proliferation and survival of memory CD8+ T cells and enhance the formation of long-term immunological memory which may lead to sustained anti-cancer immune response. The combination of NKTR 255 and TIL's could improve proliferation and persistence of cellular therapies leading to enhanced anti-tumor activity.

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 exclude those who have used immunosuppressive medications within 14 days before tumor harvest. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

What data supports the effectiveness of the treatment C-TIL051 + Anti-PD1 Therapy for lung cancer?

Research shows that PD-1 and PD-L1 inhibitors, which are part of the treatment, have been effective in treating advanced non-small cell lung cancer (NSCLC), especially in patients with high PD-L1 expression. This suggests that combining these inhibitors with other therapies like C-TIL051 could potentially enhance treatment outcomes. ^{1 2 3 4 5}

Is the combination of C-TIL051 and Anti-PD1 Therapy safe for humans?

PD-1/PD-L1 inhibitors, used in lung cancer treatment, can cause immune-related side effects like pneumonitis (lung inflammation) and other adverse events, but these are generally manageable. In patients with autoimmune disorders, some experienced flares or immune-related side effects, but these were often mild and rarely led to stopping treatment. ^{6 7 8 9 10}

What makes the C-TIL051 + Anti-PD1 therapy unique for lung cancer treatment?

C-TIL051 + Anti-PD1 therapy is unique because it combines tumor-infiltrating lymphocytes (TILs), which are immune cells that can attack cancer, with anti-PD1 therapy, which helps the immune system recognize and fight cancer cells. This combination aims to enhance the immune response against lung cancer, potentially offering a novel approach compared to standard treatments that focus solely on PD-1/PD-L1 inhibition. ^{1 2 5 11 12}

Eligibility Criteria

This trial is for adults with stage IV or recurrent non-small cell lung cancer (NSCLC) who haven't responded to standard treatments. They must have a heart function test showing normal results, adequate organ and marrow function, and no serious infections like HIV or hepatitis. Pregnant women, those unwilling to use contraception, and patients with certain lung conditions or recent immunosuppressive drug use are excluded.

Inclusion Criteria

Your recent lung function tests show that your lungs are working well.

My lung cancer is confirmed to be stage IV or recurrent NSCLC with adenocarcinoma or squamous cell type.

Your heart tests from the past 6 months show that your heart is working well and there are no signs of heart problems.

Exclusion Criteria

Any condition that may interfere with evaluation of study treatment, safety or study results

I am allergic to certain cancer drugs or their ingredients.

I am willing to use contraception during and 6 months after the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Tumor Sample Collection

Participants provide a tumor sample prior to the start of any treatment which will be used to make the C-TIL051

1 week

Standard of Care Treatment

Participants receive standard of care treatment until their lung cancer no longer responds

Variable

Lymphodepletion Chemotherapy

Participants receive chemotherapy (called lymphodepletion) for 3 days followed by 2 days of rest

1 week

C-TIL051 Infusion and NKTR-255 Administration

C-TIL051 is infused on day 0 followed by NKTR-255 (IL-15) about 12 to 24 hours later

1 day

Pembrolizumab Treatment

Pembrolizumab is administered every 3 weeks for up to 2 years

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

Treatment Details

Interventions

• C-TIL051

Trial Overview The study tests C-TIL051 combined with NKTR-255 and anti-PD1 therapy in NSCLC patients whose cancer hasn't improved with standard care. It involves taking a tumor sample to create C-TIL051, chemotherapy preparation, followed by infusions of C-TIL051 and NKTR-255, then regular Pembrolizumab injections for up to two years.

Participant Groups

Group I: C-TIL051 Experimental Treatment 1 Intervention

C-TIL051 plus IL-15 (NKTR-255) and Pembrolizumab

Who Is Running the Clinical Trial?

AbelZeta, Inc.

Lead Sponsor

Trials

1

Recruited

20+

AbelZeta Inc.

Lead Sponsor

Cellular Biomedicine Group, Inc.

Lead Sponsor

Trials

3

Recruited

270+

Nektar Therapeutics

Industry Sponsor

Trials

59

Recruited

9,900+

Howard W. Robin

Nektar Therapeutics

Chief Executive Officer since 2007

B.S. in Accounting and Finance from Fairleigh Dickinson University

Dr. Dimitry Nuyten

Nektar Therapeutics

Chief Medical Officer since 2022

MD

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]

In a study of 74 patients with stage III non-small cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy, high density of CD8+ tumor-infiltrating lymphocytes (TILs) was found to be a significant predictor of better progression-free survival (PFS) and overall survival (OS), while PD-L1 expression did not correlate with these outcomes.

Patients with low PD-L1 expression and high CD8+ TIL density had the best survival rates, suggesting that assessing both PD-L1 and CD8+ TILs could serve as a valuable predictive biomarker for treatment efficacy in stage III NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Tokito, T., Azuma, K., Kawahara, A., et al.[2022]

A total of 686 clinical trials are currently investigating anti-PD-(L)1 agents for intrathoracic tumors, with a significant focus on non-small cell lung cancer (NSCLC), indicating a robust interest in this area of immunotherapy.

The majority (81%) of these trials are exploring combination treatments, often pairing PD-(L)1 blockade with chemotherapy or other immunotherapies, highlighting a trend towards more comprehensive treatment strategies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Landscape of Immunotherapy Trials Involving the Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Axis in Intrathoracic Tumors. Kareff, SA., Samtani, S., Burotto, M., et al.[2022]

In a review of 23 randomized controlled trials involving 15,797 patients, PD-1 inhibitors significantly improved overall survival (OS) by an average of 4.80 months compared to standard care, while PD-L1 inhibitors improved OS by 2.59 months.

PD-1 inhibitors were found to provide greater OS benefits than PD-L1 inhibitors, suggesting that PD-1 inhibitors may be the preferred choice for treating advanced non-small-cell lung cancer (NSCLC), especially in patients with varying PD-L1 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relative and absolute benefit of programmed death receptor-1 vs programmed death ligand 1 therapy in advanced non-small-cell lung cancer: A systematic review and meta-analysis. Yi, K., Zhu, Q., Kuang, YK., et al.[2021]

PD-L1 is a critical factor in regulating T-cell activation and immune response, particularly in non-small cell lung cancer (NSCLC), where higher PD-L1 expression is associated with better responses to PD-1 inhibitors like pembrolizumab.

The study emphasizes the importance of assessing PD-L1 expression levels across different lung cancer subtypes, as this can significantly influence treatment decisions and the effectiveness of immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 Over-Expression Varies in Different Subtypes of Lung Cancer: Will This Affect Future Therapies? Ullah, A., Pulliam, S., Karki, NR., et al.[2022]

In a review of 22 clinical trials involving 2,231 patients with advanced non-small cell lung cancer, the incidence of all-grade pneumonitis was found to be 2.9% for patients receiving PD-1 and PD-L1 inhibitors, which is significantly higher than the incidence in those receiving standard chemotherapy (OR=2.35).

While pneumonitis and other immune-related adverse effects (IRAEs) can be severe, the overall incidence of treatment-related deaths was low at 0.7%, indicating that while these therapies can have serious side effects, they are generally rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis. Hu, YB., Zhang, Q., Li, HJ., et al.[2022]

In a meta-analysis of 4413 patients from 8 randomized controlled trials, PD-1/PD-L1 inhibitors showed a significantly lower risk of all-grade adverse events (66.20% vs. 86.08%) and high-grade adverse events (14.26% vs. 43.53%) compared to chemotherapy, indicating a better safety profile.

While PD-1/PD-L1 inhibitors are generally safer, they are associated with a unique set of immune-related adverse events (irAEs) that can be severe, such as pneumonitis and thyroid dysfunction, which clinicians need to monitor closely to manage patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. Luo, W., Wang, Z., Tian, P., et al.[2021]

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 56 patients with advanced non-small-cell lung cancer (NSCLC) and concurrent autoimmune disease (AID) treated with PD-1 or PD-L1 inhibitors, 55% experienced an AID flare or immune-related adverse event (irAE), but most were manageable and did not lead to treatment discontinuation.

The overall response rate to PD-(L)1 therapy in this population was 22%, indicating that while there are risks, the treatment can still be effective for patients with NSCLC and AID.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. Leonardi, GC., Gainor, JF., Altan, M., et al.[2022]

In a study of 191 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors, those who experienced immune-related adverse events (irAEs) had significantly better treatment outcomes, with an objective response rate of 42.0% compared to 25.8% in those without irAEs.

The presence of irAEs was associated with improved progression-free survival, suggesting that these adverse events may indicate a more effective immune response to the treatment, although they did not correlate with overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China. Chen, X., Nie, J., Dai, L., et al.[2022]

Inhibition of the PD1/PDL1 pathway shows promise in treating non-small cell lung cancer (NSCLC), with anti-PD1 antibody nivolumab achieving objective responses in 13-18% of patients who had previously failed treatment, and anti-PDL1 antibodies showing similar responses of 6-22%.

While these therapies can restore immune response against tumors, they also carry risks of new adverse events, including autoimmune diseases, and further research is needed to clarify treatment duration and evaluation criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy in non-small cell lung cancer: inhibition of PD1/PDL1 pathway]. Guilleminault, L., Carmier, D., Heuzé-Vourc'h, N., et al.[2018]

Lung cancer cells express both membrane-bound PD-L1 and soluble PD-L1, which significantly inhibit the proliferation of T lymphocytes, suggesting a mechanism for immune evasion by tumors.

The study found that activated T lymphocytes showed high levels of PD-1 expression, and blocking PD-L1 with an antibody could partially restore T cell proliferation, indicating potential therapeutic strategies to enhance anti-tumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes]. Shi, MH., Xing, YF., Zhang, ZL., et al.[2021]

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

Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. [2022]

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

Current Landscape of Immunotherapy Trials Involving the Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Axis in Intrathoracic Tumors. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The relative and absolute benefit of programmed death receptor-1 vs programmed death ligand 1 therapy in advanced non-small-cell lung cancer: A systematic review and meta-analysis. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

PD-L1 Over-Expression Varies in Different Subtypes of Lung Cancer: Will This Affect Future Therapies? [2022]

6. China pubmed.ncbi.nlm.nih.gov

Evaluation of rare but severe immune related adverse effects in PD-1 and PD-L1 inhibitors in non-small cell lung cancer: a meta-analysis. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. [2021]

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

Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Immunotherapy in non-small cell lung cancer: inhibition of PD1/PDL1 pathway]. [2018]

12. China pubmed.ncbi.nlm.nih.gov

[Effect of soluble PD-L1 released by lung cancer cells in regulating the function of T lymphocytes]. [2021]