ANTIPARASITIC AGENT IVERMECTIN SYNERGIZES WITH IMMUNE-CHECKPOINT INHIBITORS IN A REFRACTORY COLORECTAL CANCER METASTATIC MODEL

SOBOL NT; SOLERNÓ LM; MARTÍNEZ GA; GOTTARDO MF; SEGATORI V; LLAVONA C; ALONSO DF; GARONA J

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAI&FAIC SAFIS 2022; 2022

Sociedad Argentina de Investigación Clínica

Immunotherapies based on immune checkpoint inhibitors (ICIs)have revolutionized colorectal cancer (CRC) management. Unfor-tunately, therapeutic benefits are limited to patients with DNA mis-match repair (MMR) deficiency. In this regard, the repurposed anti-parasitic drug ivermectin (IVM) has been proposed as a co-adjuvantagent in oncology, considering its potential impact on immunogeniccell death (ICD) induction and reversal of drug resistance. Our aimwas to explore IVM antineoplastic activity, particularly in combina-tion with αPD-1 based ICI, using the highly metastatic CT-26 mod-el, a murine KRASmut and MMR-proficient CRC cell line with limitedresponse to immunotherapy and cytotoxic agents. In vitro, CT-26showed a high sensitivity to IVM, obtaining an IC50 of 10.9 μM aftera 72h-exposure. Treatment with low concentrations of IVM was alsoassociated with a reduction in tumor chemotaxis and colony-forma-tion ability, impaired tumor cell metabolism and an increased secre-tion of proinflammatory and immunostimulatory molecules, such asTNF-α and IL-6. In vivo, immunocompetent syngeneic mice wereinjected i.v. with CT-26 cells and, after confirming metastatic colo-nization in the lung by histological studies at day 7, they were sub-jected to different treatments; Saline vehicle (control group), IVM(10 mg/kg i.p.), αPD-1 (5 mg/kg i.p.) and IVM plus αPD-1. AlthoughIVM and αPD-1 monotherapies reduced the metastatic burden by85% and 63%, respectively, the combined therapy completely inhib-ited the formation of metastatic macronodules (>2mm) in the lung.S.c. preimmunization using CT-26 cells treated ex vivo (24h) with ahigh cytotoxic IVM concentration one week prior to i.v. re-challengewith viable cells led to full protection against CRC lung metastases,postulating ICD as a possible mechanism of action (p