# Determinants of CD8+ T Cell Aging and Reduced Function in B Cell Cancer

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $121,500

## Abstract

Determinants of CD8+ T cell Aging and Reduced Function in B cell Cancer
Summary
Chimeric antigen receptor (CAR)-engineered T cells provide a breakthrough for personalized
cancer therapy. In this strategy, a patient's own T cells are genetically reprogrammed to recognize
and kill antigen-expressing tumor cells. Robust clinical responses are seen with CAR T therapy
of acute lymphocytic leukemia (ALL) in children and young adults, but only a small subset of
individuals with advanced-age B cell cancers such as multiple myeloma (MM) and chronic
lymphocytic leukemia (CLL) experience remission. These malignancies represent a challenge in
that initial generation of CAR T cells is not possible in many elderly patients due to poor
proliferative capacity in association with accelerated aging phenotypes and transcriptomic
signatures enriched in genes that drive senescence and cell cycle arrest, as indicated by our
preliminary data. Furthermore, in vivo expansion of CAR T cells in these individuals is modest,
which may be attributed to senescent proliferative arrest and premature loss of early memory T
cells. Our previous studies have indicated that in CLL, durable remission was associated with
higher peak CAR T cell replicative capacity, greater long-term persistence, and modulation of
specific T cell pathways. For example, disruption of TET2, which encodes an enzyme involved in
CpG demethylation, was associated with a notable T cell expansion in a CLL patient undergoing
successful therapy, thus marking an epigenetic pathway for future modulation to improve
therapeutic efficacy. Because a significant portion of the aging population of MM and CLL patients
does not experience therapeutic levels of CAR T cell expansion and anti-tumor activity, it is
important to investigate factors leading to accelerated aging of CD8+ T cells in the setting of these
malignancies. In the course of other studies we have devised a series of methods to
systematically determine how MM and CLL may contribute to the process of CD8+ T cell aging.
We thus propose the following Specific Aims: Aim 1. We will examine the impact of MM and CLL
on immune aging as it relates to CD8+ T cell differentiation state, telomere length, p16INK4A levels,
and T cell receptor (TCR) repertoire diversity in MM and CLL patients relative to age-matched
healthy controls. Aim 2. We will characterize the epigenetic and transcriptional landscapes of
major CD8+ T cell subsets in MM and CLL patients compared to age/gender-matched healthy
subjects and explore the influence of disease on underlying networks that regulate
immunosenescence. Aim 3. We will determine if strategies that may restore the normal replicative
lifespan of CD8+ T cells such as enhancing telomerase, inhibiting TET2 and/or modulating the
pathways identified in Aim 2 translate into improved anti-tumor function. These studies will allow
us to gain a deeper understanding of how these cancers affect CD8+ T cell aging to bring about
dysfunction throug...

## Key facts

- **NIH application ID:** 9950959
- **Project number:** 5U01AG066100-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CARL H. JUNE
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $121,500
- **Award type:** 5
- **Project period:** 2019-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950959

## Citation

> US National Institutes of Health, RePORTER application 9950959, Determinants of CD8+ T Cell Aging and Reduced Function in B Cell Cancer (5U01AG066100-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9950959. Licensed CC0.

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