Cancer immunotherapy represents a promising and rapidly developing approach for the treatment of oncological diseases. Among the methods of personalized adjuvant immunotherapy, neoantigenic peptide-based drugs have demonstrated substantial efficiency. These drugs are designed to target mutant proteins arising from somatic alterations in the genome of tumor cells and thus stimulate immune response against tumor tissues. The methods of individual screening for potentially immunogenic mutations are mostly based on next-generation exome sequencing of tumor samples, which is a complex and costly procedure for clinical application. Targeted gene sequencing panels limited to a certain set of genes represent a reasonable alternative to WES. Targeted sequencing is also more efficient when there is a low amount of the sample DNA available. We have estimated the potential efficiency of targeted oncological panels in terms of somatic neoantigen profiling in colorectal cancer (colon and rectal adenocarcinoma). The clinical practice of identification of frequent somatic variants does not provide enough data for designing an efficient personalized drug when applied to low and medium mutated cancers such as colorectal cancer. Our analysis of 11 commercially available panels containing different number of genes has shown that neither the larger size of a panel nor its initial customization for colorectal cancer provides a significantly better estimation of an individual somatic mutation profile. The optimal approach is to use the general-purpose medium-sized cancer panels (2300-11200 amplicons and/or 150-600 genes). These panels allow to detect a sufficient number of immunogenic epitopes (>3) per patient for over 30-50% of patients.
Immunoterapevticheskie podkhody k lecheniiu onkologicheskikh zabolevaniĭ iavliaiutsia mnogoobeshchaiushchim stremitel'no razvivaiushchimsia napravleniem. Odnim iz metodov personalizirovannoĭ ad"iuvantnoĭ immunoterapii iavliaetsia stimulirovanie immunnogo otveta na mutantnye belki opukholi s pomoshch'iu preparatov na osnove neoantigennykh peptidov, sinteziruemykh opukholevymi kletkami v rezul'tate poiavleniia somaticheskikh mutatsiĭ v ikh genome. Tekhnologii skrininga individual'nykh dlia patsienta i potentsial'no neoantigennykh mutatsiĭ osnovany na vysokoproizvoditel'nom sekvenirovanii, chashche vsego opukholevogo ékzoma, chto iavliaetsia slozhnoĭ i dorogostoiashcheĭ protseduroĭ. Vozmozhnym al'ternativnym resheniem iavliaetsia ispol'zovanie dlia sekvenirovaniia targetnykh paneleĭ, ogranichennykh izbrannymi genami. Primenenie takikh paneleĭ mozhet byt' bolee priemlemym i v tekh sluchaiakh, kogda po tem ili inym prichinam ne udaetsia poluchit' dostatochnoe kolichestvo opukholevoĭ DNK. My otsenili potentsial primeneniia targetnykh paneleĭ onkologicheskoĭ napravlennosti dlia detektsii neoantigennykh somaticheskikh variantov pri kolorektal'nom rake (adenokartsinoma tolstoĭ i priamoĭ kishki). Primeniaemye v klinicheskoĭ praktike metody detektirovaniia nekotorykh chastykh somaticheskikh variantov ne pozvoliaiut poluchit' neoantigennyĭ profil' opukholi, dostatochnyĭ dlia dizaĭna éffektivnogo preparata v sluchae malo- i srednemutirovannykh rakov, k kotorym otnositsia kolorektal'nyĭ rak. Provedennyĭ nami analiz 11 dostupnykh targetnykh paneleĭ, otlichaiushchikhsia po chislu okhvatyvaemykh imi genov, pokazal, chto kak bol'shoĭ razmer paneli, tak i spetsializatsiia sostava paneli pod konkretnoe zabolevanie (kolorektal'nyĭ rak) ne daet printsipial'nykh preimushchestv pri otsenke individual'nogo neoantigennogo profilia. Optimal'nym dlia dannoĭ zadachi iavliaetsia ispol'zovanie onkopaneleĭ obshchego profilia, soderzhashchikh srednee (2300-11200) kolichestvo amplikonov i/ili okhvatyvaiushchie 150-600 genov. Takie paneli pozvoliaiut detektirovat' dostatochnoe kolichestvo immunogennykh épitopov (>3) dlia doli patsientov, prevyshaiushcheĭ pokazatel' v 30-50%.
Keywords: colorectal cancer; immunotherapy; neoantigens; sequencing; targeted panels.