A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses

Abstract

Cancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but the outcomes have been unimpressive, perhaps because these peptides elicit predominantly CD4+ T cell responses. We hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improved anti-tumor responses. Here, we have designed SLP-containing cationic lipoplexes (SLP–Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using the G12D KRAS mutations as neoantigens, we found that vaccination of mice with naked synthetic peptides harboring the G12D mutation with CpG adjuvant stimulated mainly CD4+ T cell responses with limited tumor growth inhibition. On the other hand, immunization with SLP–Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combination of the SLP–Lpx vaccines with a checkpoint inhibitor led to profound growth suppression of established tumors. These studies suggest that preferential targeting of peptides derived from neoantigens to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

“…Follow-up immunotherapy with anti-CTLA4 antibody resulted in complete remission of gp70-negative CT26 tumors in all mice in this study ( 178 ). In an inducible lung adenocarcinoma mouse model, vaccination using the G12D KRAS mutations as neoantigens and a novel synthetic long peptide-containing cationic lipoplex-based delivery platform stimulated both CD4 + and CD8 + T cell response and suppressed tumor growth, while combination with checkpoint inhibitor furthered such suppression ( 179 ). Similarly, both CD4 + and CD8 + T cell response has been reported in recent clinical studies following neoantigen-specific vaccination, across multiple cancer types.…”

Cationic Nanoparticle-Based Cancer Vaccines

“…During the past decades, a large number of nanoparticle types have been developed to target DCs and induce cellular immune responses. Among these nanoparticles, cationic particles are of special interest, because they have shown to have superior immunostimulatory properties as compared to their neutral and anionic analogues and have proven to be potent inducers of antigen-specific T-cells [ 9 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Recent preclinical and clinical studies have shown that cationic nanoparticles offer clinically applicable vaccine formulation platforms [ 9 , 10 , 36 , 37 , 38 ].…”

Beyond Just Peptide Antigens: The Complex World of Peptide-Based Cancer Vaccines

“…The charge, size, surface molecules and delivery mechanism of liposomes are all tailorable – this feature allows a liposome to mimic the size and surface markers of a pathogen for example ( 96 , 97 ). As particulate systems can protect peptides from degradation and control their release, liposomes provide peptides greater access to the spleen and lymph nodes which contain a higher proportion of cross-presenting DCs ( 98 , 99 ). Upon internalisation, the liposome can continue to promote antigen cross-presentation by enabling its peptide cargo to escape from the lysosome into the cytosol, a key step in antigen cross-presentation and stimulation of a robust CD8 + T cell response ( 100 ).…”

“…In a study that looked at mutant KRAS SLP-Liposomes, the use of KRAS G12 mutant SLPs alone resulted in primarily a CD4 + response ( 99 ). It was only upon the SLP being bound to the liposome did the vaccine produce a strong CD8 + response, albeit at the slight expense of CD4 + activity ( 99 ).…”

“…In a study that looked at mutant KRAS SLP-Liposomes, the use of KRAS G12 mutant SLPs alone resulted in primarily a CD4 + response ( 99 ). It was only upon the SLP being bound to the liposome did the vaccine produce a strong CD8 + response, albeit at the slight expense of CD4 + activity ( 99 ). The authors did note an increase in tumour PD-1 and TIL exhaustion markers, which resulted in a therapeutic response that slowed tumour growth but did not lead to regression ( 99 ).…”