Abstract
Effect of a novel expansion process on tumor-infiltrating lymphocyte (TIL) polyfunctionality, cytotoxicity, and expansion, while preserving cells in a less differentiated and more stem-like phenotype.
Author
person
Andrew Yuhas
Iovance Biotherapeutics, Inc., San Carlos, CA
info_outline
Andrew Yuhas, Joe Dean, Tim Erickson, Marcus Machin, Mohammed Alkhouli, Joe Yglesias, Rafael Cubas
Full text
Authors
person
Andrew Yuhas
Iovance Biotherapeutics, Inc., San Carlos, CA
info_outline
Andrew Yuhas, Joe Dean, Tim Erickson, Marcus Machin, Mohammed Alkhouli, Joe Yglesias, Rafael Cubas
Organizations
Iovance Biotherapeutics, Inc., San Carlos, CA
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
This study is sponsored by Iovance Biotherapeutics
Background:
Adoptive cell therapy using autologous TIL has shown durable responses in patients with metastatic melanoma and some epithelial tumors (Chesney
JITC
2022; Schoenfeld SITC 2021; O’Malley SITC 2021). Data suggest that maintaining a higher proportion of less differentiated and more stem-like TIL can associate with persistence and response in patients with metastatic melanoma (Krishna
Science
2020; Rosenberg
Clin Cancer Res
2011). Here, we describe a novel TIL expansion process that increases TIL expansion and preserves cells in a less-differentiated and more stem-like phenotype with enhanced functional output.
Methods:
Tumors of various histologies, including lung, breast, and renal cancer, were fragmented and expanded using either a standard process or a newly developed process that uses a different combination of cytokines during the pre-rapid expansion protocol (pre-REP) stage and another combination of cytokines and a pathway inhibitor during the REP stage to control T-cell activation and differentiation. The expansion potential, viability, and phenotypic and functional attributes of the final TIL products were evaluated by a variety of assays.
Results:
When compared with standard TIL expansion, the novel process increased yield and viability while preserving TIL in a less differentiated and more functional state, as evidenced by increased expression of the memory-associated markers CD27, CD28, CD62L, and IL-7R, with reduced expression of the activation markers CD38, CD39, and CD69, and lower levels of the inhibitory markers LAG3, TIM3, TIGIT, and TOX. Importantly, the novel process led to a pronounced increase in the tumor-homing marker CXCR3 as well as TIL polyfunctionality as evidenced by increased co-expression of IFNγ, TNFα, and IL-2 while showing an enrichment in genes associated with stem-like cells and a reduction in exhaustion-associated genes. Pseudotime trajectory analysis also demonstrated that the new expansion process maintained TIL in a less differentiated and more stem-like state. Together, these phenotypic and functional characteristics translated into increased cytotoxicity even after repeated stimulation.
Conclusions:
Our novel TIL expansion process improves multiple metrics that correlate with both TIL persistence and response, including enhanced polyfunctionality, reduced inhibitory receptor expression and a less differentiated and more stem-like phenotype, while increasing yield. These effects may translate into a more vigorous and less differentiated TIL infusion product with improved cytotoxicity and persistence.
Clinical status
Pre-clinical
1 organization
2 drugs
9 targets
Organization
Iovance BiotherapeuticsDrug
CytokinesTarget
IL-2Target
TNFαTarget
TIM3Target
TIGITTarget
IL-7RTarget
LAG3Target
TOXTarget
CXCR3Target
IFNγ