# Metabolic Reprogramming of Tumor Infiltrating Lymphocytes for Adoptive Immunotherapy

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $357,994

## Abstract

Abstract
Adoptive cell transfer using autologous tumor infiltrating lymphocytes (TIL) represents a personalized cancer
immunotherapy strategy targeting shared and unique tumor antigens expressed by a patient's cancer. Although
originally developed for cutaneous melanoma therapy, we recently reported TIL therapy can be effective against
metastatic uveal melanoma (UM), a cancer with low mutational burden and resistance to conventional
immunotherapies. A significant limitation in improving upon these results is that the vast majority of antigen
experienced TIL will undergo cell death shortly following infusion. Only a small subset persist as long-lived
memory cells. This may stem from the limited metabolic reserve of highly differentiated effector T cells (TEFF).
Chronic antigen exposure can result in deficiencies in nutrient sensing and flux through critical bioenergetic and
biosynthetic pathways that support T cell activation, proliferation, and effector functions. Ex vivo metabolic
reprograming could rescue “exhausted” TEFF and promote development of long-lived memory cells following
adoptive transfer. Our long-term goal is to develop clinically relevant approaches that promote the metabolic
fitness of human TIL following adoptive transfer. 4-1BB (CD137) co-stimulatory signaling can transiently improve
the metabolic capacity of human tumor specific CD8+ TEFF. Our preliminary findings demonstrate that this
metabolic improvement is dependent upon a novel mechanism employing the activity of the mitochondrial
enzyme, arginase 2 (ARG2). Thus, the specific objective of this grant is to further characterize the role of ARG2
in reprogramming the fate and function of highly differentiated TEFF. Our central hypothesis is that ARG2 is the
critical mediator of the improved metabolism found in TEFF following 4-1BB co-stimulation. Since 4-1BBL
expression is often deficiently expressed by tumors, we, consequently, postulate that bioengineering TEFF to
conditionally express ARG2 upon TCR stimulation will reprogram their cellular metabolism in the tumor
microenvironment, improving in vivo persistence and function. We anticipate that these studies will enhance the
metabolic fitness of TIL for future adoptive transfer clinical trials. To test our hypothesis, we propose the following
Specific Aims: Aim 1. Identify key transcriptional regulators linking 4-1BB co-stimulation with ARG2 activity in
human TEFF cells. Aim 2. Characterize the downstream metabolic and cellular effects of ARG2 expression in TEFF
cells. Aim 3. Determine the safety and efficacy of adoptive transfer of human TIL bioengineered to express ARG2
in patient derived tumor xenograft models. Collectively, the completion of these studies will demonstrate the
essential role of enhanced ARG2 expression in promoting and sustaining T cell metabolism. Bioengineered
expression of ARG2 could markedly improve adoptive immunotherapy with TIL.

## Key facts

- **NIH application ID:** 9975113
- **Project number:** 5R01CA233521-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Udai S Kammula
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,994
- **Award type:** 5
- **Project period:** 2019-07-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975113

## Citation

> US National Institutes of Health, RePORTER application 9975113, Metabolic Reprogramming of Tumor Infiltrating Lymphocytes for Adoptive Immunotherapy (5R01CA233521-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975113. Licensed CC0.

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