Bespoke immunotherapy: how close are we?

Please see the article by Narita et al pp. 348–359.

Recent trials have highlighted that glioblastoma’s (GBM) relatively low mutational load and immunologically “cold” tumor microenvironment have made the effectiveness of therapies that nonspecifically boost immune responses, such as immune checkpoint inhibitors (ICIs), less dramatic in these tumors. This may not come as a surprise, as ICIs have historically been more successful in tumors with high mutational loads and strong baseline antitumor responses.¹ Personalized vaccines seek to convert a traditionally “cold” tumor into an immunoresponsive “hot” tumor through amplification of preexisting immune responses and by inducing de novo responses against new antigenic targets through epitope spread.² In this issue, Narita et al present the results of their randomized, double-blinded, phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent GBM.³ While the trial failed to meet either primary or secondary endpoints, its results may give insights into strategies to improve the efficacy of targeted and personalized immunotherapy.

The trial attempts to tailor to the diversity of GBM tumors and host immune repertoires by utilizing a PPV approach in which 4 HLA-matched peptides were selected from a set of warehouse peptides (ITK-1) based on preexisting host immunity. Patients with positive immunoglobulin G response to at least 2 of the 12 peptides were randomized to receive PPV or placebo injections. In total, 58 patients received PPV with a median overall survival (OS) of 8.4 months. There was no significant difference in either median OS or progression-free survival (PFS) between the 2 groups. Interestingly, the selection of SART2-93 peptide was the most predominant negative prognostic factor of OS in patients who received PPV. The authors note that patients with SART2-93 as part of their vaccine did not have significant preexisting immunity against the vaccinated peptides, as evidenced by no detectable cytotoxic T lymphocyte activity against the remaining 11 peptides and low preexisting immunoglobulin G levels to the 4 selected peptides. Immunologic biomarkers of OS in PPV-treated patients included lower percentage of immunosuppressive monocytes and higher percentages of activated T helper cells prior to vaccination.

While the trial failed to show significant improvement in PFS or OS in the PPV group, it illustrates the importance of the immunogenicity of selected vaccine antigens in eliciting a clinically beneficial immune response. Peptide vaccine pools such as ITK-1 consist of prearranged tumor-associated antigens, which are nonmutated proteins that are aberrantly expressed in tumors but shared between the tumor and self, and therefore may exhibit central tolerance and generate less robust immunogenicity.⁴ Tumor-specific neoantigens are mutations that are uniquely expressed by the tumor and have more immunogenicity potential than tumor-associated antigens. The concept of neoantigen vaccines was first implemented in melanoma with the rationale of utilizing individualized tumor-specific mutations to generate peptides that are unique to each patient’s tumor to elicit more specific and robust antitumor immune responses.⁵ Keskin et al recently reported results from a phase I study of an analogous personalized neoantigen vaccine (NeoVax) in newly diagnosed GBM.⁶ In parallel, the Glioma Actively Personalized Vaccine Consortium (GAPVAC) reported data from a phase I trial of vaccines based on individualized selection of both immunogenic tumor-associated and tumor-specific peptides to exploit the full repertoire of tumor antigens.⁷ Both groups showed sustained peripheral neoantigen-specific CD4+ and CD8+ T-cell responses with increase in the number of tumor infiltrating lymphocytes including neoantigen-specific T cells. With recent advancements in genomic sequencing and bioinformatics, high throughput sequencing of individual tumors to identify tumor-specific mutations is becoming widely available and affordable. However, current methods of predicting neoantigens and assessing peptide immunogenicity are far from perfect. There is ongoing debate whether major histocompatibility complex binding affinity or complex stability best determines antigen immunogenicity and whether clonal or subclonal neoantigens generate more effective antitumor immunity.⁸ With the gaining momentum of personalized immunotherapy, there is need for further validation and improvement of neoantigen prediction pipelines and determination of therapeutically relevant neoantigen immunogenicity to advance the accuracy of personalized vaccines.

While PPVs may generate systemic and intratumoral neoantigen-specific immune responses, the ITK-1 trial ultimately failed and all the patients in the NeoVax trial ultimately had tumor recurrence, indicating that induced T-cell response alone is insufficient in generating clinically relevant antitumor activities. This is likely due to the diverse global immunosuppression induced by GBMs. Studies of peripheral and tumor infiltrating T cells in GBM show evidence of significant exhausted states with coexpression of multiple immune checkpoint molecules.⁹ The NeoVax study suggests that this holds true for vaccine stimulated neoantigen-specific T cells as well; and even once they reach the tumor microenvironment, they are further exposed to immunosuppressive factors, including glioma-associated macrophages, microglia, and inhibitory ligands.⁶ These results suggest that while PPVs have the potential to favorably boost the antitumor response through T-cell mediated tumor destruction and subsequent release of secondary epitopes, the ultimate success of glioma immunotherapy likely will require combination therapies to address the complex factors contributing to T-cell dysfunction. With the increasing number of therapies aimed to deplete or inhibit immunosuppressive myeloid populations and promising preclinical results, combination therapy aimed to reverse both glioma myeloid and lymphoid immunosuppression holds potential for future clinical benefit. Additionally, phase I trials are currently under way evaluating the efficacy of neoantigen-based vaccines such as NeoVax in combination with ICIs in newly diagnosed GBMs (NCT03422094, NCT02287428). While we await the results from these trials, additional considerations for the success of glioma immunotherapy include refinement of neoantigen selection, identification of immune biomarkers of response, and optimization of iatrogenic factors of immunosuppression such as immunosuppressive corticosteroids and chemoradiation. Temozolomide and radiation, part of the GBM treatment regimen, have been shown to have conflicting effects on immunotherapy, with the potential to be counterproductive or synergistic.¹⁰ Therefore, there is need to further determine the optimal timing of integration of immunotherapy into standard of care. Findings from this current trial emphasize personalized therapies that consider the genetic heterogeneity of GBM, tailor patient selection based on tumor and immune biomarkers, and counter the complex glioma-associated immunosuppression as promising strategies for improving the efficacy of immunotherapies for patients with these tumors.

Funding

M.L. is funded by Arbor, Aegenus, Altor, BMS, Accuray, and DNAtrix.

Conflict of interest statement. The authors have no conflict of interest relating to this topic. M.L. is a consultant for Tocagen, SQZ Technologies, Stryker, and Baxter.

Authorship statement. Both C.J. and M.L. contributed to the writing of the manuscript. Both authors have read and approved the final version of the manuscript. The text is the sole product of the authors and no third party had input or gave support to its writing.