Oral Presentation Melbourne Immunotherapy Spring Symposium 2025

Combination Immune Checkpoint Blockade in People with HIV – Analysis of antigen-specific CD8+ T-cells (128639)

Hannah AD King 1 , Shihan Li 2 , Rachel D Pascoe 1 , Céline Gubser 1 , Carolin Tumpach 1 , Jenny L Anderson 2 , Jan Schröder 2 , Sharon R Lewin 1 3 4
  1. Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  2. Computational Sciences Initiative (CSI), The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  3. Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  4. Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia

T cell function is impaired in people living with HIV (PWH) due to an increased expression of immune checkpoints, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), leading to immune exhaustion. To obtain effective immune control of HIV, strategies to reverse this exhaustion and increase T cell function are required. One promising approach to improve immune function is blocking immune checkpoints via the administration of monoclonal antibodies that prevent binding to their receptor, thereby reversing T cell exhaustion.

As part of a prospective longitudinal clinical trial of PWH on ART with cancer (AIDS Malignancy Consortium-095 Study), participants received anti-PD-1 (nivolumab) every 2 weeks, with some participants additionally receiving anti-CTLA-4 (ipilimumab) every 6 weeks. We sorted HIV-tetramer+ and tetramer- CD8+ T-cells from 7 participants receiving combination treatment, and 2 participants receiving anti-PD-1 alone, both before and following infusions at weeks 0 and 6. We then performed single-cell RNA sequencing.

In total CD8+ T cells, combination immune checkpoint blockade did not alter the frequency of cellular subsets nor the cellular phenotype within these clusters. In tetramer+ CD8+ T-cells, we observed a modest, transient increase in effector memory T cell frequency following initial immune checkpoint blockade. This contrasts with our previous data from participants who received nivolumab alone. Here, the frequency of tetramer+ effector CD8+ T cells decreased concurrently with the emergence of an exhaustion progenitor cluster with an interferon-stimulated gene signature.

In PWH, we observed minimal changes in the phenotype of antigen-specific T cells following combination immune checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies, in contrast with our previous data on single PD-1 blockade. Future work will analyse samples from a greater number of participants to enable detailed characterisation of antigen-specific cells following single and combination immune checkpoint blockade.