A clinical trial of therapeutic vaccination in lymphoma with serial tumor sampling and single-cell analysis.

"the scrna-seq data are deposited in the ncbi database of genotypes and phenotypes (dbgap accession number phs002188)."

"Conflict-of-interest disclosure: The authors declare no competing financial interests."

"Janssen provided financial support and ibrutinib for the clinical trial. TriSalus Life Sciences provided SD101 for the clinical trial. The study was supported by 10.13039/100000002National Institutes of Health (NIH) 10.13039/100000054National Cancer Institute grant R35 CA197353, Leukemia & Lymphoma Society grant TRP 6539-18, and the Hoogland Lymphoma Research Fund (R.L.); and was supported at different times by NIH National Cancer Institute grant K08CA252637, National Heart, Lung, and Blood Institute grant 5T32HL120824-04, and an American Cancer Society Postdoctoral Fellowship PF-17-239-01-LIB (T.S.); and by a Mildred Scheel postdoctoral fellowship from the 10.13039/501100005972Deutsche Krebshilfe (70113507) (S.H.). The content is solely the responsibility of the authors and does not represent the official views of any funding agency listed."

"In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at 1 tumor site, which can then tackle the disease throughout the body. Here, we report clinical and biological results of a phase 1/2 ISV trial in patients with low-grade lymphoma, combining an intratumoral toll-like receptor 9 (TLR9) agonist with local low-dose radiation and ibrutinib (an inhibitor of B- and T-cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including 1 complete response. All patients experienced tumor reduction at distant sites. Single-cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher major histocompatibility complex class II expression on tumor cells, enhanced T-cell and natural killer cell effector function, and reduced immune suppression from transforming growth factor β and inhibitory T regulatory 1 cells. Although changes at the local injected site were more pronounced, changes at distant uninjected sites were more often associated with clinical responses. Functional immune response assays and tracking of T-cell receptor sequences provided evidence of treatment-induced tumor-specific T-cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. The trial was registered at www.clinicaltrials.gov as #NCT02927964."