Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.

BACKGROUND

Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.

METHODS

Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety.

RESULTS

17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers.

CONCLUSIONS

TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

Informations de copyright

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: RA has consulting or advisory roles with Novartis, Erasca, and Iovance and receives institutional research funding from Bristol Myers-Squibb, Roche, Novartis, OnKure, Iovance and Obsidian. MJO has consulting or advisory role with Bristol Myers Squibb, Roche/Genentech, Gritstone Bio, MedImmune, Novartis, Promega, Spectrum Pharmaceuticals, Array BioPharma, Janssen, Pfizer, 3D Medicines, Merck, Eisai and research funding from Bristol Myers Squibb, Merck, Roche, MedImmune, Phanes Therapeutics. C-WDT is a consultant for PanTher Therapeutics and receives research funding from SirTex. AJ has received institutional research funding from Bristol Myers-Squibb, Iovance, Merck, Pfizer, Aravive, Macrogenics, AstraZeneca, Imunon, Avenge Bio, Greenfire Bio, and Break Through Cancer. He has received consulting fees from Guidepoint, Alkermes, Gerson Lehrman Group, Adicet Bio, Theolytics, Avenge Bio, and Greenfire Bio. CB received research funding from Iovance Biotherapeutics and Obsidian Therapeutics, and reports consulting or advisory roles with Myst Therapeutics and Turnstone Biologics. CB, M-AF and DS-T are now currently employees of the Cell Therapy Manufacturing Center (CTMC), Houston, Texas, USA, a joint venture between MD Anderson Cancer Center and Resilience. CLH reports receiving funding to institution from Avenge Bio, Dragonfly, BTG, Sanofi, Obsidian and Iovance; stock options from Briacell as an SAB member; travel support/honoraria from the Hope Foundation and the Society for Immunotherapy of Cancer outside the scope of the submitted work.