Modulation of the immune system has been demonstrated as a powerful approach to treating cancer. Immunotherapies are generally classified as active or passive according to their ability to trigger the immune system. During the last decades, information regarding the relevance of aberrant glycosylation as a major player in tumour biology encouraged expectations for the development of new therapeutic strategies directed at glycans. Several tumour-associated carbohydrate antigens (TACAs) have been identified and validated as suitable immunotherapeutic targets, leading to promising therapeutic developments. It is known that TACAs are poorly immunogenic since they are unable to trigger a proper immune response. Given that they are not presented by major histocompatibility complex (MHC) molecules and that they induce immune tolerance, the development of active immunotherapeutic strategies against TACAs is a real challenge. However, antitumor strategies based on mimetics of TACAs have been developed and show promising results. Active immunotherapies based on TACAs mimicry can currently be grouped into strategies based on the use of mimetic peptides and anti-idiotype (Id) antibodies. In this review, we discussed the scientific basis on which these strategies are based and the available therapeutic options that have shown the best results in preclinical studies and in clinical practice.

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.