N-glycolylneuraminic acid (NeuGc) is a sialic acid molecule present in mammalian cells as terminal constituents of membrane glycoconjugates such as gangliosides and glycoproteins. Although the role of NeuGc-containing glycoconjugates in human cancer is still under investigation, gangliosides such as NeuGcGM3 has been consistently reported as a tumor antigen in various epithelial and neuroectodermal malignancies, including non-small cell lung cancer (NSCLC). Interestingly, NeuGc-glycoconjugates are abundant in aggressive neoplasms, but they are usually absent in normal human tissues. In contrasts to most mammals, human beings lack the key enzyme that catalyzes N-glycolylation of sialic acid. Cancer cells can favor NeuGc intake from diet sources, thus allowing the expression of NeuGc-containing glycoconjugates. Racotumomab is an anti-NeuGc anti-idiotype monoclonal antibody that has been approved in Latin American countries as maintenance immunotherapy for advanced NSCLC. Combinatorial approaches involving long-term immunization against tumor-specific antigens together with the anti-PD1 immune-checkpoint inhibitor pembrolizumab is an attractive strategy for immunotherapy. In this work, we have examined the antitumor activity of racotumomab in combination with anti-PD1 therapy, using the 3LL Lewis lung carcinoma as a preclinical model of NSCLC in C57BL/6 mice. Immunization with either weekly or biweekly s.c. doses of racotumomab at 50-200 μg/dose formulated in aluminum hydroxide (racotumomab-alum) demonstrated a significant antitumor effect against the progression of lung tumor nodules (p<0.05, ANOVA followed by Tukey). Similarly, checkpoint blockade with an anti-mouse PD1 monoclonal antibody injected i.p. at 200 μg/dose exerted a comparable antitumor effect in this 3LL lung model (p<0.01, unpaired t-test). Interestingly, sequential administration of anti-PD1 therapy followed by repeated immunizations with racotumomab-alum was highly effective against lung nodules and well tolerated, showing a reduction in nodules formation of 62 and 45% compared to anti-PD1 or racotumomab-vaccinated groups, respectively (p<0.01, ANOVA followed by Tukey). Our preclinical data provide support for the combination of anti-PD1 checkpoint blockade with the anti-idiotype monoclonal antibody racotumomab in advanced NSCLC, since combination treatment has a significant additive antitumor effect compared to each individual treatment.
Citation Format: Valeria I. Segatori, Cynthia A. Gulino, Carla S. Capobianco, Selene Rojo, Gretel M. Ferreira, Héctor A. Cuello, Mariano R. Gabri, Daniel A. Alonso. Racotumomab and PD-1 blockade combination exhibits an additive antitumor effect in a non-small cell lung cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6648.