Abstract 1685: Effects of anti-ctla-4 and anti-pd-1 on memory T-cell differentiation and resistance to tumor relapse
Authors: Mok Stephen , Duffy Colm R. , Allison James P. 
Published: July 2017

Abstract
The FDA has begun to expand the approved uses of immune checkpoint blockade antibodies targeting CTLA-4 and PD-1. Blocking either checkpoint relieves the negative regulation of T-cells resulting in significant responses in patients with cancer. Data has now begun to emerge regarding differences between these two therapies. While αPD-1 therapy has a greater response rate (~30% vs. 11%) according to RECIST criteria, recent reports have suggested responses to αPD-1 may not be as durable as αCTLA-4. 25% of patients who initially responded to αPD-1 have tumor relapse within 24 months. In contrast, the 3-year survival rate of patients treated with αCTLA-4 is at least ~25% suggesting a durable response. Previous studies in bacterial or chronic LCMV infectious models have shown that αCTLA-4 can increase CD8+ memory T-cell formation, whereas genetic ablation of PD-1 on T-cells often promotes the terminally differentiated exhausted CD8+ T-cell phenotype, while attenuating memory T-cell formation. However, the mechanism which leads to relapse following αPD-1 treatment in tumor models is not clear. The goal of this project is to understand how immunotherapies shape memory T-cell formation and how that relates to the mechanism of tumor relapse.
To test whether αCTLA-4 or αPD-1 can induce a better memory T-cell response, mice were vaccinated with irradiated B16F10 murine melanoma cells and treated αCTLA-4 or αPD-1. Mice were re-challenged with B16F10 80 days after vaccination. Although both αCTLA-4 and αPD-1 improved tumor rejection compared with controls, αCTLA-4 treated mice exhibited superior tumor control compared to αPD-1 (p&lt;0.0005) suggesting the memory T-cell response mediated by αCTLA-4 is more durable. In order to test whether this memory T-cell response is antigen-specific, mice were re-challenged with unrelated MC38 or 3LL cancer cells. The antibody treated groups did not show improved antitumor effect compared with vaccine control (p&gt;0.5). To test whether the frequency of memory T-cells recruited to the re-challenged tumor could affect memory T-cell response, antigen-specific pmel-1 T-cells were infused to mice following vaccination with αCTLA-4 or αPD-1. Our result suggested that there were more tumor-infiltrating pmel-1 T-cells in the αCTLA-4 treated group compared to the αPD-1 treated group (p&lt;0.05). In order to augment the durability of αPD-1 treatment, αPD-1 was combined with αCTLA-4 following vaccination. The combined treatment group has superior antitumor response compared to that with αPD-1 (p&lt;0.000003) and overlapped with the αCTLA-4 treated group (P&gt;0.05) during re-challenge, indicating that the effect of the combined treatment is dominated by αCTLA-4.
Collectively, our studies facilitate the design of combination immunotherapy treatments that enhance both response rates and generation of memory T-cells to prevent relapse.
Citation Format: Stephen Mok, Colm R. Duffy, James P. Allison. Effects of anti-ctla-4 and anti-pd-1 on memory T-cell differentiation and resistance to tumor relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1685. doi:10.1158/1538-7445.AM2017-1685