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Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC)

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE148482 | GEO | 2020/04/11

REPOSITORIES: GEO

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Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [WXS]

Project description:This study demonstrates two fundamental tenets of immunotherapy: vaccines targeting any tumor antigen will not be as effective as those targeting true oncogenic drivers and neither the stimulation of tumor-specific T-cells nor the blockade of a key immune checkpoint is enough to overcome the layers of immune suppression by itself. It provides single cell genetic evidence that vaccination alone generates a population of CD8 T-cells incapable of long-term tumor control due to the activation of numerous immune dysfunction pathways within the tumor. These promising studies have led to the initiation of a Phase II clinical trial testing a novel HER2 vaccine in combination with Pembrolizumab (NCT03632941) to determine if this combination can elicit effective anti-tumor immunity while minimizing off-target immune responses in patients with advanced HER2+ BC.

2020-04-11 | GSE148478 | GEO

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [scRNA-Seq]

2020-04-11 | GSE148480 | GEO

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [RNA-Seq]

2020-04-11 | GSE148477 | GEO

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and ?PD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

Project description:PurposeDespite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.Experimental designOur models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2?16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination.ResultsWe found that only vaccination targeting HER2?16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2?16 vaccination was combined with ?PD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with ?PD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.ConclusionsCombining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).

| S-EPMC7483405 | biostudies-literature

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC)

Project description:Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC)

| PRJNA624350 | ENA

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [WXS]

| PRJNA624344 | ENA

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [RNA-Seq]

| PRJNA624342 | ENA

Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [scRNA-Seq]

| PRJNA624354 | ENA

Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade.

Project description:In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell-like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.

| S-EPMC8045516 | biostudies-literature

Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors.

Project description:Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFN?-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFN?-expressing tumor-infiltrating CD4(+) and CD8(+) T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFN?-inducing cancer vaccines with immune checkpoint blockade.

| S-EPMC4396709 | biostudies-literature

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