Clinical Trials of TIL Therapy

The first promising results evaluating the use of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma were published in 1988.^1,2 Since 2011, trials investigating TIL therapies have continued to grow in number, with the majority of studies evaluating treatment of melanoma, non–small cell lung cancer (NSCLC), ovarian cancer, and head and neck cancer.³ TIL therapy involves harvesting infiltrated lymphocytes from tumors, culturing and expanding the cells, and infusing them back into the patient.³ It is a personalized, therapy given once that can target a wide array of cancer antigens.^3,4

TIL Therapy in Advanced Melanoma

TIL therapy in combination with high-dose interleukin-2 (IL-2) has demonstrated antitumor activity in patients with melanoma, with an average reported objective response rate (ORR) of 43%.^5,6 In heavily pretreated patients with melanoma, durable responses have been achieved in approximately 20% to 30% of patients.⁶

A phase 2 study (NCT02360579) evaluated the efficacy and safety of lifileucel in 66 patients with metastatic melanoma who experienced disease progression after treatment with an anti–PD-1 agent and, in those with BRAF V600E-mutant disease, a BRAF or MEK inhibitor.^7,8 All patients enrolled had at least 1 prior therapy, including an inhibitor of PD-1 (100%), CTLA-4 (80%), or BRAF/MEK (23%).8 The study included a cohort f patients who received a single infusion of lifileucel in combination with 1 week of nonmyeloablative lymphodepletion, followed by up to 6 doses of IL-2.8 At a median follow-up of 28 months, the ORR per investigator assessment and RECIST v1.1 was 36.4%, including 3 complete responses and 21 partial responses (PRs).⁸ Median duration of response (DOR) was not reached.⁸ During this long-term follow-up, no new safety signals associated with lifileucel were identified. The adverse event (AE) profile was consistent with the underlying disease, lymphodepletion, and receipt of IL-2.^8,9

NSCLC and melanoma share similarities in terms of tumor mutational burden (TMB), sensitivity to immune checkpoint inhibitors (ICIs), and T cell–mediated antigen recognition. Therefore, TIL therapy may be a treatment option in metastatic NSCLC, as it has already shown promise in melanoma.^10-12

TIL Therapy in NSCLC

Growing evidence suggests that response to TIL therapy is determined by the number of targeted neoantigens, the presence of corresponding neoantigen-directed T cells, tumor mutational loads, and predicted neoantigen loads. Approximately 38% to 42% of patients with NSCLC are reported to be TMB-high (defined as ≥ 10 mut/Mb) as compared with 52% of patients with melanoma.¹³ TMB is also used to estimate the capacity of neoantigen production in tumor cells, which tends to be higher in smokers than in nonsmokers.^14,15

Clinical Trials Investigating TIL Therapy in NSCLC

IOV-COM-202

The phase 2 study IOV-COM-202 (NCT03645928) is evaluating the autologous TILs lifileucel (LN-144), LN-145, and LN-145-S1 as combination therapy with ICIs and as monotherapy. This trial includes cohorts with locally advanced or metastatic NSCLC.¹⁶

Sixteen patients received TIL infusion after their NSCLC had progressed despite initial treatment with the ICI nivolumab. Eleven of the ¹⁶ patients experienced tumor regression after TIL treatment. At 18 months follow-up, complete tumor response was ongoing in 2 patients; 2 others showed either a PR or maintained clinical remission.¹⁷ Treatment-related AEs were primarily due to lymphodepletion and IL-2 treatment, both of which were required prior to TIL reinfusion. Common nonhematologic AEs included nausea and diarrhea.¹¹

Cohort 3B included 28 patients with advanced or metastatic NSCLC who were previously treated with an ICI and/or oncogene-directed therapy. The ORR in the full-analysis set was 21.4%. With a median follow-up of 8.2 months, median DOR was not reached, and 83% of responses were ongoing. Safety was consistent with underlying disease and AEs resulting from the combination of nonmyeloablative lymphodepletion and IL-2 treatment.¹⁸

Future cohorts will study TIL therapy in different contexts. Cohort 3A will evaluate TIL therapy in combination with the ICI pembrolizumab in patients whose NSCLC is ICI-naïve. Cohort 3C will examine whether treatment with the ICIs ipilimumab and nivolumab prior to harvesting the tumor will increase T-cell infiltrate to the tumor, which could provide a larger initial population of TILs.¹⁶

IOV-LUN-202

The phase 2 trial IOV-LUN-202 trial (NCT04614103) will evaluate use of the TIL therapy LN-145 in patients with metastatic NSCLC without driver mutations who have documented radiographic disease progression on or after first-line therapy (ICI plus chemotherapy with or without bevacizumab).¹⁹ The trial is currently enrolling patients across 4 cohorts; all patients will have pathologically confirmed stage IV NSCLC.

Cohort 1 will include patients with NSCLC whose tumors do not express PD-L1 and those with unknown PD-L1–expression status. Patients must meet study requirements for tumor resection. Cohort 2 will include patients with NSCLC whose tumors express PD-L1. These patients must also meet study requirements for tumor resection. Cohort 3 will include patients with similar characteristics as those in cohort 1, but cohort 3 patients should not meet study requirements for surgical tumor resection, and their TILs will be grown from a tumor biopsy sample. Cohort 4 will involve patients who were enrolled in cohorts 1 to 3 and were previously treated with LN-145 but who require retreatment.¹⁹

DELTA-2

The DELTA-2 trial (NCT05393635) will be a phase 1 study of the autologous TIL ITIL-168 given in combination with pembrolizumab. Cohort 3 of this trial will evaluate ITIL-168 in patients with NSCLC whose disease has progressed during or after use of platinum-based chemotherapy and an ICI. Patients with targetable mutations in proteins (eg, EGFR or ALK) will be required to have NSCLC that has progressed on EGFR/ALK-targeted therapy and platinum-based chemotherapy.²⁰

Phase 1a/1b study of ITIL-306

ITIL-306 is a form of TIL therapy that is engineered to express a costimulatory antigen receptor (CoStAR) targeting folate receptor α (FOLR1). Recent preclinical data reported at the 2022 American Society for Clinical Oncology Annual Meeting suggest that in combination with TCR-specific binding CoStAR expression increased TIL proliferation and antitumor activity.21 An ongoing phase 1a/1b study (NCT05397093) is evaluating ITIL-306, and cohort 2 of the phase 1b portion will study use of the therapy in patients with NSCLC whose disease has progressed after 1 prior line of platinum-based doublet chemotherapy and an ICI. Patients with targetable mutations are required to have NSCLC that has progressed on targeted therapy in addition to a platinum-based doublet chemotherapy.²²

TILs in Preclinical Development

IOV-4001 is a PDCD1-knockout TIL therapy, which was developed to enhance the efficacy of TIL therapy and eliminate the need for anti-PD-1 treatment and avoid systemic AEs associated with anti-PD-1/PD-L1 therapy. Preclinical data presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting showed promising antitumor activity in murine models.^23,24

References

1. Hulen TM, Chamberlain CA, Svane IM, Met O. ACT up TIL now: the evolution of tumor-infiltrating lymphocytes in adoptive cell therapy for the treatment of solid tumors. Immuno. 2022;1:194-211. doi:10.3390/immuno1030012

2. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676-1680. doi:10.1056/NEJM198812223192527

3. Wang S, Sun J, Chen K, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med. 2021;19:140. doi:10.1186/s12916-021-02006-4

4. Fardis M, DiTrapani K, Finckenstein FG, Chartier C. Current and future directions for tumor infiltrating lymphocyte therapy for the treatment of solid tumors. Cell Gene Ther Insights. 2020;6(6):855-863. doi:10.18609/cgti.2020.088

5. Dafni U, Michielin O, Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol. 2019;30(12):1902-1913. doi:10.1093/annonc/mdz398

6. Kumar A, Watkins R, Vilgelm AE. Cell therapy with TILs: training and taming T cells to fight cancer. Front Immunol. 2021;12:690499. doi:10.3389/fimmu.2021.690499

7. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). ClinicalTrials.gov. Updated March 25, 2021. Accessed September 8, 2022. https://www.clinicaltrials.gov/ct2/show/NCT02360579

8. Chesney JA, Larkin JM, Kirkwood JM, et al. Abstract CT008: lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patient with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Cancer Res. 2021;81(suppl 13);CT008. doi:10.1158/1538-7445.AM2021-CT008

9. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612

10. Federico L, Haymaker CL, Forget MA, et al. A preclinical study of tumor-infiltrating lymphocytes in NSCLC. J Clin Oncol. 2018,36(suppl S5):161. doi:10.1200/JCO.2018.36.5_suppl.16

11. Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27(8):1410-1418. doi:10.1038/s41591-021-01462-y

12. Robertson J, Salm M, Dangl M. Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer. Immunooncol Technol. 2019;3:1-7. doi:10.1016/j.iotech.2019.09.003

13. Shao C, Li G, Huang L, et al. Prevalence of high tumor mutational burden and association with survival in patients with less common solid tumors. JAMA Netw Open. 2020;3(10):e2025109. doi:10.1001/jamanetworkopen.2020.25109

14. Zou XL, Li XB, Ke H, et al. Prognostic value of neoantigen load in immune checkpoint inhibitor therapy for cancer. Front Immunol. 2021;12:689076. doi:10.3389/fimmu.2021.689076

15. Ye L, Creaney J, Redwood A, Robinson B. The current lung cancer neoantigen landscape and implications for therapy. J Thorac Oncol. 2021;16(6):922-932. doi:10.1016/j.jtho.2021.01.1624

16. Study of autologous tumor infiltrating lymphocytes in patients with solid tumors. ClinicalTrials.gov. Updated June 15, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT03645928

17. Adoptive cell therapy plus checkpoint inhibitors show promise in non-small cell lung cancer. Moffitt Cancer Center. August 12, 2021. Accessed July 29, 2022. https://moffitt.org/newsroom/press-release-archive/adoptive-cell-therapy-plus-checkpoint-inhibitors-show-promise-in-non-small-cell-lung-cancer/

18. Schoenfeld A, Lee S, Paz-Ares L, et al. First phase 2 results of autologous tumor-infiltrating lymphocyte monotherapy in patients with advanced immune checkpoint inhibitor-treated, non-small cell lung cancer. J Immunother Cancer. 2021;9(suppl 2):A486. doi:10.1136/jitc-2021-SITC2021.458

19. Autologous LN-145 in patients with metastatic non-small-cell lung cancer. ClinicalTrials.gov. Updated August 9, 2022. Accessed September 8, 2022. https://clinicaltrials.gov/ct2/show/NCT04614103

20. ITIL-168 in advanced solid tumors (DELTA-2). ClinicalTrials.gov. Updated May 26, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT05393635

21. Moon OR, Qu Y, King MG, et al. Antitumor activity of T cells expressing a novel anti-folate receptor alpha (FOLR1) costimulatory antigen receptor (CoStAR) in a human xenograft murine solid tumor model and implications for in-human studies. J Clin Oncol. 2022;40(suppl 16):2535. doi:10.1200/JCO.2022.40.16_suppl.2535

22. ITIL-306 in advanced solid tumors. ClinicalTrials.gov. Updated July 11, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT05397093

23. A study to investigate the efficacy and safety of an infusion of IOV-4001 in adult participants with unresectable or metastatic melanoma or stage III or IV non-small-cell lung cancer. ClinicalTrials.gov. Updated July 26, 2022. Accessed July 29, 2022. https://clinicaltrials.gov/ct2/show/NCT05361174

24. Natarajan A, Veerapathran A, Wells A, et al. Abstract 2746: preclinical activity and manufacturing feasibility of genetically modified PDCD-1 knockout (KO) tumor-infiltrating lymphocyte (TIL) cell therapy. Cancer Res 2022;82(suppl 12):2746. doi:10.1158/1538-7445.AM2022-2746