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Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

ABSTRACT: Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

PROVIDER: PRJNA1159374 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30623386.fastq.gz	Fastqsanger.gz
	SRR30623387.fastq.gz	Fastqsanger.gz
	SRR30623388.fastq.gz	Fastqsanger.gz
	SRR30623389.fastq.gz	Fastqsanger.gz
	SRR30623390.fastq.gz	Fastqsanger.gz

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Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [neoAgSpCD8Tcells]

Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) synthetic long peptide (SLP) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Effective NeoAg SLP vaccines and ICT required both CD8 and CD4 T cells. Both NeoAg SLP vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg SLP vaccination. Further, we found that NeoAg SLP vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. While NeoAg SLP vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS+Bhlhe40+ Th1-like CD4 T cells. Although effective NeoAg SLP vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg SLP vaccines maintained, rather than suppressed as observed with ICT, M2-like CX3CR1+CD206+ macrophages expressing the TREM2 receptor. While combining NeoAg SLP vaccination with ICT induced superior efficacy compared to either therapy in isolation, we also assessed a novel combination of NeoAg SLP vaccination and anti-TREM2, demonstrating enhanced efficacy of this combination associated with a decrease in intratumoral CX3CR1+CD206+ macrophages and promotion of IFN-g+ NeoAgspecific CD8 T cells. These findings highlight the utility of combining NeoAg SLP vaccines with ICT, as well as novel combinatorial therapy targeting the myeloid compartment via TREM2 blockade to enhance NeoAg SLP vaccine efficacy.

2024-10-10 | GSE276904 | GEO

Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

2024-10-10 | GSE276902 | GEO

Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

Project description:Comparing Neoantigen Cancer Vaccines and Immune Checkpoint Therapy Unveils an Effective Vaccine and Anti-TREM2 Macrophage-Targeting Dual Therapy [CD45]

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Personal Neoantigen Cancer Vaccines

Project description:Personal Neoantigen Cancer Vaccines

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Comparing neoantigen cancer vaccines and immune checkpoint therapy unveils an effective vaccine and anti-TREM2 macrophage-targeting dual therapy.

Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines maintain CX3CR1+CD206+ macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1+CD206+ macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy.

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Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer

Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

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Project description:The purpose of this study is 1) to evaluate the feasibility of manufacturing a patient-specific neoantigen cancer vaccine, which involves predicting the patient’s neoantigens and generating a vaccine that encodes the predicted neoantigens; and, 2) to identify and select patients who may be eligible for a shared neoantigen cancer vaccine where their tumor contains a specific shared mutation and who have the correct HLA allele capable of presenting the neoantigen derived from the tumor-specific mutation.

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