Abstract LB-188: Selective targeting of SIRP alpha induces potent memory antitumor immune responses without presenting hematological toxicity (2017)

Abstract Targeting immune checkpoints of the adaptive immunity has shown great therapeutic efficacy to fight cancers, but in a limited proportion of patients. Myeloid cells represent the most abundant immune cell type in many solid tumors, and are often associated with a poor outcome. Interaction of SIRPalpha (SIRPα), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response, involved in the regulation of macrophages, dendritic cells and neutrophils function (e.g. phagocytosis). Thus, combining immunotherapies targeting both adaptive and innate immune cells represents a promising therapeutic strategy against cancer. Since agents targeting CD47 (anti-CD47 or SIRPa-Fc) recently experienced hematological toxicity (anemia or thrombocytopenia), we evaluated the preclinical safety and efficacy of an antagonistic anti-SIRPa monoclonal antibody (mAb). Here, we found that administration of anti-SIRPa mAb at high dose (10 mg/kg) in healthy or tumor-bearing mice did not modify red blood cells and platelets numbers, hematocrit and hemoglobin levels, while in parallel anti-CD47 mAbs rapidly induced anemia within three days, owing to the high expression of CD47 on red blood cells. Next, we evaluated the therapeutic potential of antagonist anti-SIRPa mAbs in combination with adaptive immune checkpoint inhibitors (anti-PD-L1 mAb) or an adaptive immune checkpoint agonist (anti-4-1BB mAb) using an orthotopic hepatocellular carcinoma (HCC) preclinical model in immunocompetent mice. Monotherapy with antagonist anti-SIRPa mAbs prolonged survival in 25% of mice but did not induce remission (p&amp;lt;0.01). While PD-1 blockade alone was also poorly effective in this model (MST: 22 days, n=8), combination with SIRPα blockade induced durable remission in 60% of mice (p&amp;lt;0.05). Association of SIRPα blockade with 4-1BB agonist was highly efficient with 80% of long-term remission (p&amp;lt;0.01) while monotherapy with 4-1BB mAb led to tumor elimination in only 26% of mice (ns). Mice presenting a remission after selective SIRPα blockade in combination with PD-L1 or 4-1BB agents acquired a robust memory immune responses mediated, at least, by T lymphocytes since a second tumor challenge (performed up to one month after treatment withdrawal) was always rejected (p&amp;lt;0.01). In addition, adoptive transfer of T lymphocytes from cured mice in naïve untreated mice protected them from orthotopic HCC development. In conclusion, we showed that targeting selectively SIRPa is devoid of hematological toxicity and that combination of immunotherapies targeting both adaptive and innate immune cells is promising to generate robust antitumor memory immunity. Citation Format: Vanessa Gauttier, Sabrina Pengam, Sophie Conchon, Bernard Vanhove, Nicolas Poirier. Selective targeting of SIRP alpha induces potent memory antitumor immune responses without presenting hematological toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2017-LB-188