Botensilimab, an Fc-Enhanced Anti-CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy.

This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.

TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.

TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes.

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

Unlabelled: In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses.

NK cells with decreased expression of multiple activating receptors is a dominant phenotype in pediatric patients with acute lymphoblastic leukemia.

NK cells have unique attributes to react towards cells undergoing malignant transformation or viral infection. This reactivity is regulated by activating or inhibitory germline encoded receptors. An impaired NK cell function may result from an aberrant expression of such receptors, a condition often seen in patients with hematological cancers.

Immuno-PET Monitoring of CD8 T Cell Infiltration Post ICOS Agonist Antibody Treatment Alone and in Combination with PD-1 Blocking Antibody Using a Zr Anti-CD8 Mouse Minibody in EMT6 Syngeneic Tumor Mouse.

Purpose: The presence and functional competence of intratumoral CD8 T cells is often a barometer for successful immunotherapeutic responses in cancer. Despite this understanding and the extensive number of clinical-stage immunotherapies focused on potentiation (co-stimulation) or rescue (checkpoint blockade) of CD8 T cell antitumor activity, dynamic biomarker strategies are often lacking. To help fill this gap, immuno-PET nuclear imaging has emerged as a powerful tool for in vivo molecular imaging of antibody targeting.

Emergence of the CD226 Axis in Cancer Immunotherapy.

In recent years, a set of immune receptors that interact with members of the nectin/nectin-like (necl) family has garnered significant attention as possible points of manipulation in cancer. Central to this axis, CD226, TIGIT, and CD96 represent ligand (CD155)-competitive co-stimulatory/inhibitory receptors, analogous to the CTLA-4/B7/CD28 tripartite. The identification of PVRIG (CD112R) and CD112 has introduced complexity and enabled additional nodes of therapeutic intervention.

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.

The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs).

Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody.

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4.

Harnessing co-stimulatory TNF receptors for cancer immunotherapy: Current approaches and future opportunities.

Co-stimulatory tumor necrosis factor receptors (TNFRs) can sculpt the responsiveness of T cells recognizing tumor-associated antigens. For this reason, agonist antibodies targeting CD137, CD357, CD134 and CD27 have received considerable attention for their therapeutic utility in enhancing anti-tumor immune responses, particularly in combination with other immuno-modulatory antibodies targeting co-inhibitory pathways in T cells. The design of therapeutic antibodies that optimally engage and activate co-stimulatory TNFRs presents an important challenge of how to promote effective anti-tumor immunity while avoiding serious immune-related adverse events.

Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans.

CD4(+) regulatory T cells (Tregs) are critical for maintaining self-tolerance and function to prevent autoimmune disease. High densities of intratumoral Tregs are generally associated with poor patient prognosis, a correlation attributed to their broad immune-suppressive features. Two major populations of Tregs have been defined, thymically derived natural Tregs (nTregs) and peripherally induced Tregs (iTregs).

Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia.

Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified.

Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature.

We show here that fundamental aspects of antitumor immunity in mice are significantly influenced by ambient housing temperature. Standard housing temperature for laboratory mice in research facilities is mandated to be between 20-26 °C; however, these subthermoneutral temperatures cause mild chronic cold stress, activating thermogenesis to maintain normal body temperature. When stress is alleviated by housing at thermoneutral ambient temperature (30-31 °C), we observe a striking reduction in tumor formation, growth rate and metastasis.

Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis.

Myeloid-derived suppressor cells (MDSCs) comprise immature myeloid populations produced in diverse pathologies, including neoplasia. Because MDSCs can impair antitumor immunity, these cells have emerged as a significant barrier to cancer therapy. Although much research has focused on how MDSCs promote tumor progression, it remains unclear how MDSCs develop and why the MDSC response is heavily granulocytic.

Identification of a G-CSF-Granulocytic MDSC axis that promotes tumor progression.

Myeloid-derived suppressor cells (MDSC) induced during neoplasia display potent pro-tumorigenic activities. Tumor-derived factors influence MDSC development, yielding monocytic and granulocytic subsets. In contrast to monocytic MDSC, little is known about how granulocytic MDSC develop.

Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism.

Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models.