Abstract 1052P
Background
Iovance’s autologous tumor-infiltrating lymphocyte (TIL) product has reported efficacy results in metastatic melanoma and cervical cancer patients that reflect an ORR of 36.4% and 44%, respectively. While this appears superior to standard of care, we seek further improvements by creating a new generation of TIL. One potential limitation of TIL therapy is inactivation by the PD-1/PD-L1 pathway, which provides rationale for combining TIL with PD-1 blockade. Here, we abrogate PD-1 within the TIL product to reduce PD-L1-dependent TIL inactivation. Consequent TIL killing of cancer cells may be enhanced while avoiding the toxicity associated with systemic anti-PD-1 therapy, thereby consolidating two complementary benefits in one treatment. For this, we performed knockout (KO) of the PDCD1 gene in TIL, utilizing transcription activator-like effector nuclease (TALEN) technology.
Methods
TIL from breast, ovarian, and lung cancers were tested. TIL were electroporated with PD-1 TALEN mRNA and expanded in culture. PD-1 KO efficiency and phenotype were evaluated by flow cytometry. Effector function of PD-1 KO TIL was verified in cell-based assays.
Results
Delivery of TALEN mRNA to TIL by electroporation was highly efficient (> 90%) and did not compromise cell viability, indicating that the full spectrum of polyclonal and diverse TIL could be targeted. Up to 72% PD-1 KO efficiency was achieved. All PD-1 KO TIL were successfully expanded through a novel process. Levels of activation/exhaustion markers in PD-1 KO TIL were comparable to controls, arguing against any compensatory mechanisms in response to decreased PD-1 expression. Most importantly, PD-1 KO TIL were highly functional in all standard assays.
Conclusions
In this first report of TALEN-mediated gene editing of polyclonal TIL, a robust protocol was established for the generation of PD-1 KO polyclonal TIL exhibiting the features of a highly active therapeutic product. These results, along with the strong rationale supporting the combination of TIL with PD-1 inhibition, support clinical testing of this approach that may enhance the potency of immunotherapy while retaining all safety aspects of conventional TIL therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Iovance Biotherapeutics, Inc.
Funding
Iovance Biotherapeutics, Inc.
Disclosure
K. Ritthipichai, M. Machin C. Chartier: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Iovance Biotherapeutics, Inc. A. Juillerat, L. Poirot: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Cellectis. M. Fardis: Speaker Bureau/Expert testimony, Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Officer/Board of Directors: Iovance Biotherapeutics, Inc.; Shareholder/Stockholder/Stock options: Gilead; Shareholder/Stockholder/Stock options: AbbVie; Officer/Board of Directors: Kartos Therapeutics.