Resistance to immune checkpoint inhibition (ICI) using antibodies against the PD-1/PD-L1 axis remains a significant clinical challenge. Here, we report that combination of anti-PD-1 with a bifunctional fusion molecule, anti-TCRβ-IL-2, comprised of a monovalent Fab that binds and activates the T-cell receptor (TCR) through distinct variable beta (Vβ) chain residues and an IL-2 molecule, mediates robust anti-tumor control in the context of ICI resistance.
Syngeneic murine models with varying levels of ICI-resistance were used to assess sensitization to ICI in combination with the anti-TCRβ-IL-2 therapy. Mechanisms of the combination therapy’s benefit were investigated by profiling tumor-infiltrating lymphocytes via flow cytometric, single cell transcriptomic, and histological analyses. Immune response efficacy and diversification was identified by the generation of multifunctional, tumor-associated antigen-specific and neoantigen-specific T-cell responses post-therapy.
Unlike anti-PD-1 therapy alone that resulted in expansion of terminally exhausted CD8
+
T cells and lack of anti-tumor effect, administration of anti-TCRβ-IL-2 followed by anti-PD-1 greatly enhanced anti-tumor efficacy leading to tumor cures and long-term protection in several murine models resistant to ICI. Analysis of tumor-infiltrating lymphocytes showed increased proliferation and markers of cytotoxicity in CD8
+
and CD4
+
T cells, reduced CD8
+
T-cell exhaustion, and decreased proportion of regulatory CD4
+
T cells in tumors of mice receiving TCRβ-IL-2 followed by anti-PD-1. Diversification of the immune response with increased number of multifunctional, neoantigen-specific T cells was observed in mice receiving anti-TCRβ-IL-2 followed by anti-PD-1, compared to each of the monotherapies.
A novel T-cell activation mechanism sensitizes refractory tumors to ICI via T-cell function revival and epitope spreading. From these results, a clinical trial is planned to evaluate the combination of an anti-TCRβ-IL-2 agent (invikafusp alfa) and anti-PD-1 in ICI-refractory non-small cell lung and castration-resistant metastatic prostate cancers.
Shantel Angstadt, Lucas A. Horn, Kristen Fousek et al.· Journal of Experimental &...· 0 citations
Endogenous retroviruses (ERVs) are remnants of germline retroviral infections that occurred over evolution and make up 5—8% of the human genome. Although ERVs are typically epigenetically silenced in healthy adult tissues, they are overexpressed in carcinomas and may represent a novel pool of immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a therapeutic target in cancer.
The expression of ERVMER34-1 in healthy adult and cancer tissues was assessed by IHC. Its immunogenicity in human PBMCs was evaluated by ELISPOT assays, and the lytic ability of specific T cells was assessed by live-cell imaging assays. In addition, a rationally designed ERVMER34-1—targeted therapeutic vaccine was tested for its ability to induce tumor clearance in two murine carcinoma models, as monotherapy or in combination with immuno-oncology agents.
The ERVMER34-1 protein is overexpressed in several human carcinomas while being absent in most healthy adult tissues. ERVMER34-1—specific T cells were detected in PBMCs of cancer patients but not healthy donors after overnight stimulation, yet reactive T cells expand readily from both groups after 7 days of in-vitro stimulation. These T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A rationally designed therapeutic vaccine targeting ERVMER34-1 mediated tumor control in two syngeneic murine tumors. When combined with checkpoint blockade, the vaccine induced tumor regression and promoted the expansion of neoepitope-reactive T cells, whose function was further enhanced by an FDA-approved IL-15 superagonist. The strong neoepitope response associates with an inflamed tumor microenvironment marked by increased CD8+ T-cell infiltration and improved tumor control.
This study supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1, which would represent a new class of therapeutic cancer vaccine targeting ERVs.
This study was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
D. Hamilton, Maria del Mar Maldonado, Renee N. Donahue et al.· Journal of Immunology· 0 citations
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