We tested a DC-based vaccine pulsed with autologous oxidized whole-tumor lysate based on earlier preliminary data that it can induce a broad immune response to multiple tumor antigens (37), a condition that could be advantageous in the context of combinatorial immunotherapy. Here, we show that such a personalized approach to cancer immunization is feasible, well tolerated, and safe either when given alone or when combined with intravenous bevacizumab and low-dose intravenous cyclophosphamide.
As previously hypothesized, we demonstrated that our vaccination approach can effectively mobilize antitumor immunity in ovarian cancer patients and that postimmunization peripheral blood T cells could recognize autologous tumor cells in addition to DCs loaded with autologous tumor lysate. In some patients that we could analyze who received vaccination for several months, we observed a progressive increase in the frequency of tumor-reactive peripheral blood. Postimmunization peripheral blood T cells were able to kill autologous tumor more effectively than preimmunization peripheral blood T cells, both in vitro and in vivo in PDX mice as demonstrated in one patient. The detection of postimmunization T cells that were reactive to either autologous tumor cells or to DCs loaded with autologous tumor lysate was associated with significantly better clinical outcome. Progression was seen among patients in whom we could not detect any such T cells postimmunization, whereas the median time to progression of those in whom we documented reactive T cells was >15 months among which one-third had not progressed at 24 months. In addition, we observed remission inversion in more than 60% of the patients who responded to vaccine.
Recently, some papers reported the successful induction of responses to tumor neoepitopes after vaccination using synthetic peptides vaccine (27, 28, 49). Here, we report that whole-tumor antigen vaccination elicits a specific response against tumor neoepitopes. We analyzed six evaluable patients in whom we could detect on-immunization T cells reactive to autologous tumor cells or to autologous DCs pulsed with autologous tumor lysate. In all these patients, we documented CD8+ responses against one or multiple neoepitopes on-immunization. Although we found that immunization induced both CD4+ and CD8+ T cells, a feature that is considered important for effective antitumor immune responses (50), our neoepitope discovery algorithm selectively assessed CD8+ responses as it was restricted to class I–restricted peptides. It is thus possible that our study underestimated the magnitude of neoepitope-specific T cells that were elicited by the immunization.
We found that many responses detected after five doses of vaccination were new responses undetectable prevaccination. However, we also saw that vaccination amplified preexisting responses to some neoepitopes, which we could already detect prevaccination. In two cases analyzed in detail, we found a marked increase in the avidity of on-immunization T cells, which recognized cognate neoepitope peptide at more than 100-fold lower concentrations. To understand more how OCDC expanded preexisting T cell response to neoepitopes, we sorted cells specific to one neoepitope, which were then subjected to TCR sequencing to learn more on their clonal repertoire. We identified few immunodominant clones in preimmunization and postimmunization samples, but there was no overlap between the two conditions, indicating that, in fact, the observed amplified response was due to the priming of novel high-avidity T cell clones. We thus applied molecular modeling to compute the strength of interactions between each TCR and its cognate pMHC formed by the neoepitope and its assigned HLA-A*0206. Postimmunization TCRs were predicted capable of higher strength interactions with the cognate pMHC as we have previously demonstrated (51), further substantiating that increased avidity of on-immunization T cells was due to the newly detected clones with higher-affinity TCR. Collectively, these data provide evidence that DCs pulsed with oxidized tumor lysate can effectively induce the detection of novel T cell clones against multiple tumor neoepitopes, which can exhibit high-affinity TCRs and lead to high-avidity responses.
The clinical efficacy of cancer vaccines has been long debated because vaccines alone have not been efficacious in producing objective responses in the clinic (52). The advent of effective immunomodulatory molecules has, however, raised hopes that cancer vaccines could become an important partner in combinatorial approaches, and preclinical data amply support this notion (30, 53). Vaccines targeting tumor neoepitopes could be particularly promising because they could expand neoepitope-specific T cells (27–29). Expectedly, neoepitope-specific T cells could exhibit high avidity because they presumably escape thymic selection, which depletes self-recognizing clones bearing high-affinity TCRs. However, concrete evidence supporting this hypothesis is missing to date. Here, we provide evidence that DCs pulsed with whole-tumor lysate can expand novel high-avidity T cell clones with markedly high-affinity TCRs against tumor neoepitopes. These observations suggest that perhaps peripheral tolerance mechanisms suppress at the steady state the emergence of such high-affinity TCR clones, whereas exogenous DCs loaded with immunogenic lysate can drive their expansion.
The study was designed to address safety and feasibility of the combination of DCs with bevacizumab and cyclophosphamide. We pursued the above combination based on the hypothesis that cyclophosphamide would enhance vaccination, and bevacizumab could be a suitable partner for immunotherapy (41, 54) and the notion that the combination of bevacizumab and low-dose cyclophosphamide has proven safe in ovarian cancer patients (38–40, 55). In addition to providing encouraging safety data, we show that the cohort who received the full combination exhibited longer OS relative to patients who received only vaccine plus bevacizumab. The addition of low-dose cyclophosphamide resulted in more effective immunization, which was also associated with concordant serum biomarker changes. The 2-year survival of the cohort who received the full combination was considered promising, albeit preliminary, compared to literature and historic institutional controls.
Albeit the limitations that one can encounter with autologous whole-tumor antigen DC vaccines such as the lack of immunogenicity of lysates, the paucity of tumor material sufficient to produce vaccine, and the difficulty of the production itself, these pilot clinical observations along with our biological observations provide encouraging data for the pursuit of DC vaccines pulsed with autologous whole-tumor antigen in the context of personalized combinatorial immunotherapy approaches, where the mobilization of broad antitumor immunity and neoepitope-specific T cells appears as an important strategy.
Source : https://stm.sciencemag.org/content/10/436/eaao5931.full1055