1032P - Tumor-infiltrating lymphocytes with inducible membrane-tethered IL-12 cultured in optimized media exhibits superior anti-tumor activity

Background

Lifileucel is a tumor-infiltrating lymphocyte (TIL) cell therapy approved in the US for the treatment of unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF/MEK inhibitor. The current study aimed to improve TIL efficacy by: 1) enhancing potency with inducible membrane-tethered NFAT- interleukin-12 (IL-12; TeIL12); 2) improving persistence with constitutive expression of a membrane-tethered cytokine (cytokine X); and 3) increasing TIL function and yield with expansion process optimization.

Methods

Tumor tissues derived from various types of solid tumors, including non-small cell lung cancer, melanoma, and endometrial cancer, were fragmented and cultured, followed by transduction with a lentivirus vector containing TeIL12 alone, or TeIL12 bicistronically combined with cytokine X. TIL subsequently underwent a rapid expansion process in an optimized growth media and were assessed for autologous reactivity, cytotoxicity, and IL-2–independent proliferation. In vivo TIL activity was evaluated in a PDX adoptive cell transfer murine model.

Results

TeIL12 exhibited inducible expression upon stimulation with autologous tumor digest, while cytokine X was constitutively expressed. Optimized media conditions increased gene transduction efficiency and total cell yield by up to 50% and 300%, respectively. Expression of TeIL12 alone conferred superior anti-tumor activity in vivo without detectable levels of IL-12 in circulation, minimizing risk of IL-12 systemic toxicity. Dual expression of both cytokines conferred increases in interferon gamma production when stimulated with autologous tumor digest, showed improved autologous in vitro anti-tumor activity, enhanced activity in a NY-ESO-1+ A375 melanoma cell model, and improved T cell proliferation and survival in IL-2–deficient media.

Conclusions

These enhancements to TIL immunotherapy may increase efficacy and potentially allow for modification of TIL regimens including lymphodepletion and exogenously administered T cell growth factors.

Clinical trial identification

Editorial acknowledgement

Medical writing and editorial support were provided by Kalpana Vijayan, PhD, and Sarah Huh, PharmD, of Peloton Advantage, Llc, an OPEN Health Company.

Legal entity responsible for the study

Iovance Biotherapeutics, Inc., San Carlos, CA, USA.

Funding

Iovance Biotherapeutics, Inc., San Carlos, CA, USA.

Disclosure

P. Innamarato, N.J. Gilbert, A. de Mingo Pulido, M. Alkhouli, J. Fang, G. Sapena, S. Hall, H. Yin, Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Iovance Biotherapeutics, Inc.