As a 2015 paper described it, a large fraction of tumor mutations may be considered “patient-specific.”3 Furthermore, “the mutations in each tumor are so numerous and which one/subset of neoantigens would be immunogenic enough to eliminate the tumor is uncertain.” Identifying T cell reactivity against the correct neoantigens must therefore be based on the individual tumor.
That, until recently, was daunting.
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Developments in deep-sequencing genomic technologies and bioinformatics have, however, made it possible to identify mutations in an individual tumor and therefore to predict targetable neoantigens.
“Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response,” Dr Wu and coauthors wrote, “their systematic discovery and evaluation only [sic] became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules.”
Dr Wu said it took 3 to 4 months to conduct whole-exome sequencing of tumor and normal-cell DNA from each patient, to run tumoral RNA sequencing, and to synthesize peptides that would target up to 20 neoantigens per patient, stimulating both CD8+ and CD4+ T cell responses.
“We know that a strong robust immune response requires presence of both CD4 and CD8 T cells,” she said.
Using long peptides succeeded in generating this desired effect.
“In each of the 6, the responses were detectable in both CD4+ and CD8+,” Dr Wu said. “There were strong responses that came up after vaccination, not before.”
Looking ahead, the trial’s authors noted that the results demonstrate that a personal neoantigen vaccine is safe, feasible, and capable of generating powerful T cell responses. “These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies,” they wrote.
Dr Wu stressed repeatedly, however, that these findings involved only a small number of participants. Among the future avenues of exploration, she said, are possible combinations with immune checkpoint inhibitors such as the anti-PD-1 antibodies, which proved effective with the study participants who experienced recurrence.
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“The very compelling responses that we saw in the 2 patients whose tumors regressed certainly support the idea of combination of the vaccine with immune checkpoint blockers in a larger study. Our goal is to eradicate tumors with more efficacy and less toxicity.”
References
- Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217-21. doi: 10.1038/nature22991
- Fritsch EF, Hacohen N, Wu CJ. Personal neoantigen cancer vaccines: the momentum builds. Oncoimmunology. 2014;3:e29311. doi:10.4161/onci.29311
- Ito A, Kitano S, Kim Y, et al. Cancer neoantigens: a promising source of immunogens for cancer immunotherapy. J Clin Cell Immunol. 2015;6:322. doi: 10.4172/2155-9899.1000322
