IL-2/anti-IL-2 antibody complexes augment immune responses to therapeutic cancer vaccines

• 成果类型: Article
• 署名作者: Sobral, Miguel C.; Cabizzosu, Laura; Kang, Shawn J.; Ruark, Kyle; Najibi, Alex J.; Lane, Ryan S.; Vitner, Einat; Ijaz, Hamza; Dellacherie, Maxence O.; Dacus, Mason T.; Tringides, Christina M.; de Lazaro, Irene; Pittet, Mikael J.; Mueller, Soeren; Turley, Shannon J.; Mooney, David J.
• 署名单位: Harvard University; Harvard University; Roche Holding; Roche Holding USA; Genentech; Harvard University; University of Geneva; Ludwig Institute for Cancer Research; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15097
• DOI: 10.1073/pnas.2322356121
• 发表日期: 2024-11-26
• 关键词: dendritic cells; t-cells; interleukin-2; TRAFFICKING; survival

摘要

One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives similar to 3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a similar to 3-fold increase in the numbers of CD8(+) T cells and similar to 15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced similar to 5 to 30-fold greater numbers of circulating antigen-specific CD8(+) T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8(+) T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8(+) T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines.