Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies

Fc γ receptor (FcγR) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory FcγR, FcγRIIB. It remains unclear if engagement of FcγRIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory FcγRs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although FcγRIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating FcγRs were essential. Surprisingly, the dependence on activating FcγRs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating FcγRs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies

Rationale for anti-GITR cancer immunotherapy

Over the past decade, our understanding of cancer immunotherapy has evolved from assessing peripheral responses in the blood to monitoring changes in the tumor microenvironment. Both preclinical and clinical experience has taught us that modulation of the tumor microenvironment has significant implications to generating robust anti-tumor immunity. Clinical benefit has been well documented to correlate with a tumor microenvironment that contains a dense infiltration of CD8+CD45RO+ T effectors and a high ratio of CD8+ T cells to FoxP3+ Tregs. In preclinical tumor models, modulation of the GITR/GITRL axis suggests this pathway may afford the desired biological outcome of inhibiting Treg function while activating CD8+ T effector cells. This review will focus on the scientific rationale and considerations for the therapeutic targeting of GITR for cancer immunotherapy and will discuss possible combination strategies to enhance clinical benefit

A Nonproliferating Parvovirus Vaccine Vector Elicits Sustained, Protective Humoral Immunity following a Single Intravenous or Intranasal Inoculation

An ideal vaccine delivery system would elicit persistent protection following a single administration, preferably by a noninvasive route, and be safe even in the face of immunosuppression, either inherited or acquired, of the recipient. We have exploited the unique life cycle of the autonomous parvoviruses to develop a nonproliferating vaccine platform that appears to both induce priming and continually boost a protective immune response following a single inoculation. A crippled parvovirus vector was constructed, based on a chimera between minute virus of mice (MVM) and LuIII, which expresses Borrelia burgdorferi outer surface protein A (OspA) instead of its coat protein. The vector was packaged into an MVM lymphotropic capsid and inoculated into naive C3H/HeNcr mice. Vaccination with a single vector dose, either intravenously or intranasally, elicited high-titer anti-OspA-specific antibody that provided protection from live spirochete challenge and was sustained over the lifetime of the animal. Both humoral and cell-mediated Th(1) immunity was induced, as shown by anti-OspA immunoglobulin G2a antibody and preferential gamma interferon production by OspA-specific CD4(+) T cells

OX86 mediates depletion of OX40-expressing intratumoral regulatory T cells through Fc receptor co-engagement, leading to potent anti-tumor efficacy

Antibodies targeting T cell receptors have shown remarkable antitumor efficacy in preclinical and clinical studies. The engagement of activating Fc receptor (FcR)-expressing immune cells was recently shown to mediate the tumoricidal efficacy of antibodies recognizing GITR and CTLA-4. Activating FcRs facilitated the selective elimination of intratumoral T cell populations. However, it remains unclear whether FcRs contribute to the antitumor efficacy of other well-known surrogate immunomodulatory antibodies. To extend this thesis, we explored the mechanism of antitumor activity mediated by an anti-OX40 antibody (clone OX86). Like GITR and CTLA-4, OX40 was highly expressed by intratumoral T cells, particularly those of the regulatory T cell lineage. OX86 administration resulted in the strong depletion of intratumoral regulatory T cells in an activating-FcR dependent manner, which also correlated with tumor regression. We propose a paradigm, whereby antibodies targeting antigens highly expressed on intratumoral T cells leads to their elimination by FcR-expressing immune cells, which promotes antitumor immunity