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Vaccine overcomes checkpoint inhibitor limitation
response, promoting clonal diversity, consistent with selective expansion of vaccine-educated clones. This find- ing supports the hypothesis that sequential expansion of vaccine-educated lymphocytes followed by checkpoint blockade would selectively promote vaccine-mediated tumor-specific immune responses. It has been previously demonstrated that antigen-specific activation of T cells is associated with upregulation of PD-1 expression follow- ing chemotherapy among patients treated for AML,34 potentially offering a selectively timed target for PD-1 blockade. Based on this premise, checkpoint blockade in the context of vaccination may amplify the tumor-specific response in preference to nonspecific activation of autore- active clones. While a similar amplification of vaccine- induced autoimmunity is possible, there was no signifi- cant evidence of this in the vaccinated patients or the ani- mals treated with the combination. We have now initiated a clinical trial of DC/tumor vaccination in combination with PD-1 blockade in which therapeutic efficacy and tox- icity will be assessed.
Disclosures
JR has received research support from Celgene and BMS; sat on advisory boards for Amgen, Merck, BMS and Partner Tx; acted as a consultant for Parexel and Imaging Endpoint; and provided educational services for Dava Oncology. DA has received research support from Celgene and Pharmacyclics; has sat on advisory boards for Celgene, Juno, Partners Tx, Karyopharm, BMS and Aviv MedTech Ltd; and acted as a consultant for Janssen, Parexel and Takeda. GJF has patents/pending royalties on the PD-1/PD- L1 pathway from Roche, Merck, BMS, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Dako and Novartis; patents
on the TIM-3 and RGMb pathways licensed to Novartis; equity in Nextpoint and Triursus; and served on advisory boards for Roche, BMS, Xios and Origime
Contributions
DS and JL designed and performed research, interpreted data, and were responsible for preparing the manuscript. MB designed and directed research including studies related to TCR clonotype and single-cell analysis. SB performed scRNA-sequencing experi- ments and analysis. BT performed scRNA-sequencing and target- ed TCR sequencing. GC performed the mIDH2 in vivo experi- ments. RP analyzed TCR sequencing data. KM, MN, SO, MC, MW, SJ, LB, HG, AM, BT, DT and CT performed research stud- ies and participated in designing the research. BE, RS, DK and GF assisted with research design, analyzed and interpreted data, and assisted with the manuscript preparation. DA and JR designed and supervised research, the associated analysis, and manuscript preparation.
Acknowledgments
We thank the animal core facility at Beth Israel Deaconess Medical Center for assistance with imaging and treatment. We also thank Prof. Irmela Jeremias from HelmholtzZentrum München, German Research Center for Environmental Health, for generously providing the mCherry/luciferase vector.
Funding
Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award #P50CA206963. The content is solely the responsi- bility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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