# Re-engineering the tumor draining lymph node to achieve memory T cell-based adoptive immunotherapy

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Recent advances in immunotherapy have completely transformed the treatment and prognosis of
veterans with advanced melanoma. Checkpoint inhibition immunotherapy using anti-CTLA-4 and anti-PD-1
antibodies has introduced the possibility of cure for a disease that was once practically untreatable. Sadly, the
majority of veterans with metastatic melanoma will still succumb despite treatment, and incremental
improvements in efficacy have brought increasing risks of autoimmune complications. For veterans reaching
the therapeutic limits of checkpoint inhibition, it is clear that a new generation of immunotherapy is needed. In
this proposal, we examine an entirely different approach to melanoma immunotherapy. Our vision for this
approach fuses a number of long-standing and recent observations in cancer immunology. It is well known
that conventional oncological therapy and modern immunotherapy both heighten the immune response to
cancer; conventional treatments like radiation or ablation magnify tumor antigen presentation by destroying
tumor cells, and immunotherapy potentiates the activation of tumor-reactive T cells. The presentation of tumor
antigens and the activation of reactive T cells occur, in large part, in the tumor-draining lymph node – the front
line of contact between cancer and the immune system. In our previous Merit Review, we learned that a
combinatorial approach to immunotherapy using checkpoint inhibition with adoptive cell transfer generated a
qualitatively stronger immunity to melanoma antigen. We also characterized the unique oncological
advantages of tumor-reactive memory T cells over traditional effector T cells for adoptive immunotherapy. In
recent studies, we have learned that the combination of effector and memory T cells is strikingly more effective
than effector or memory T cells alone. Despite their enormous theoretical promise for immunotherapy, the
practical utility of memory T cells is handicapped by the fact that they exist in vanishingly small quantities.
Fortunately, some very recent observations have begun to shed light on the cellular metabolic pathways that
determine whether activated T cells differentiate into effector or memory T cells; intentional redirection of these
pathways can drive T cells toward either phenotype. Interestingly, the metabolic conditions that favor memory
T cell development are inherently unfavorable for cancer cell survival. Just as importantly, we have discovered
a technique for isolating and expanding large quantities of tumor-reactive effector or memory T cells using
cytokine stimulation of lymphocytes harvested from tumor-draining lymph nodes.
 We envision a new paradigm of melanoma immunotherapy. In this approach, local and systemic
oncoimmunological therapies like radiation or tumoral ablation are used with checkpoint inhibition
immunotherapy – not simply to treat tumors, but to also magnify the activation of tumor-reactive T cells within
tumor-draining lymph nodes. Next, local injectio...

## Key facts

- **NIH application ID:** 9815409
- **Project number:** 5I01BX001619-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Clifford Cho
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815409

## Citation

> US National Institutes of Health, RePORTER application 9815409, Re-engineering the tumor draining lymph node to achieve memory T cell-based adoptive immunotherapy (5I01BX001619-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815409. Licensed CC0.

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