# Preserving CTLA-4 immune checkpoint for safer and more effective cancer immunotherapy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $540,369

## Abstract

Summary
 Combination therapy with anti-CTLA-4 and anti-PD-1 mAbs has emerged as the most potent and
durable cancer immunotherapy. However, the autoimmune adverse effect associated with the combination
therapy is considerably more severe, with 50-90% of melanoma patients developing grade 3 and 4
immunotherapy-related adverse effect. A major challenge in cancer immunotherapy is how to reduce adverse
effects of the combination therapy without affecting therapeutic efficacy. This is in part related to the fact that
the mechanism by which combination therapy exacerbate irAE is not well understood. To address this issue,
we have developed a novel model in which combination therapy with anti-mouse PD-1 in conjunction with
either Ipilimumab or Tremelizumab recapitulates the severe irAE observed in clinic. Importantly, different anti-
human CTLA4 antibodies differ dramatically in irAE in this preclinical model. We have carried out extensive
preliminary studies to elucidate the molecular basis of irAE-prone vs non-prone antibodies and have shown the
antibody-mediated degradation of membrane-associated CTLA-4 as a major feature of irAE-prone antibodies.
Meanwhile, it has long been established that soluble CTLA-4 (sCTLA4) molecule is protective against
autoimmune diseases in the mice. We have obtained data that showed strong correlation between the levels
of sCTLA4 and irAE in the clinic. We further established a striking correlation between high binding to soluble
CTLA4 protein and the severity of irAE in human CTLA4KI mice. Based on these unexpected observations and
the strong therapeutic effect of CTLA4-Fc (Abatacept, marketed as Orencia) for autoimmune diseases
including irAE, we hypothesize that both cell surface and sCTLA-4 confers protection against irAE and that
sCTLA4 that evades clearance by irAE-inducing anti-CTLA-4 antibodies is a potential therapeutic for
prevention and treatment of irAE.
 Our proposal challenges the prevailing paradigm that autoimmunity and cancer immunity are based on
the same mechanism and thus intrinsically linked. More importantly, our work will have a transforming impact
in immune-oncology research, as it may offer prophylactic and treatment for irAEs associated with the most
effective immunotherapy in use in the clinic.

## Key facts

- **NIH application ID:** 10070698
- **Project number:** 1R01AI154722-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Lishan Su
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $540,369
- **Award type:** 1
- **Project period:** 2020-08-07 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070698

## Citation

> US National Institutes of Health, RePORTER application 10070698, Preserving CTLA-4 immune checkpoint for safer and more effective cancer immunotherapy (1R01AI154722-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070698. Licensed CC0.

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