Abstract CT133: Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma
Authors: Shree Tanaya , Khodadoust Michael S. , Czerwinski Debra , Frank Matthew J. , Hong Wan X. , Greenstein Rachel , Guo Summer , Long Steven , Martin Brock A. , Levy Ronald 
Published: August 2019

Abstract
In situ vaccination for the treatment of cancer aims to trigger an immune response locally that propagates systemically. We recently showed that local treatment with intratumoral CpG and low-dose radiation can elicit antitumor immune responses and global tumor shrinkage in patients with low-grade lymphoma (Frank, Cancer Discov, 2018). Ibrutinib is a small molecule that compromises B cell survival by inhibiting Bruton’s tyrosine kinase (BTK) but also modulates T cell phenotypes by inhibiting interleukin-2-inducible T-cell kinase (ITK). In a mouse model of lymphoma, systemic ibrutinib plus intratumoral CpG was curative of systemic disease in all treated mice, an effect that was fully T-cell dependent (Sagiv-Barfi, Blood, 2015). Thus, we initiated a Phase I/II clinical trial combining oral ibrutinib (560mg), intratumoral CpG (SD-101) and local low-dose radiation in patients with recurrent low-grade lymphoma (NCT02927964).
As of January 2nd, 2019, we have completed a pre-specified initial safety assessment phase and met criteria (no DLTs) to proceed to the Phase II portion. In total, 13 patients (12 FL, 1 MZL) have been enrolled thus far. All are evaluated for safety, and 12 are currently evaluable for efficacy. CT scans are performed at 3, 6, 12, 18, and 24 months. Common Terminology Criteria for Adverse Events (CTCAE) are used to track treatment-emergent safety events, and Lugano criteria (Cheson, J Clin Oncol, 2014) are used to assess response to therapy. Fine needle aspirates are obtained from CpG-injected and non-injected sites pre- and post-treatment, and analyzed by flow cytometry. When available, viably preserved tumor and peripheral blood cells are used for in vitro immune response assays.
Among 13 patients treated thus far, adverse event (AE) profiles have been similar to those seen with each therapy. No novel or synergistic AEs have been observed, and no grade 4 or 5 events have occurred. AEs have led to ibrutinib dose reduction or discontinuation in 3 patients. With a median follow-up of 7.7 months, 6 of 12 patients have obtained a partial response overall (50% ORR), and 8 of 12 have seen at least a 30% reduction in distal tumor burden, with 3 patients experiencing greater than 50% reduction in distal tumor burden. Injection of CpG decreased T follicular helper cells and increased CD4 and/or CD8 effector T cells and CD137+ activated T cells in the injected lymph node. Abscopal immune effects in distant non-injected lesions were also observed, most notably an increase in Granzyme B+ cytotoxic T cells. Treatment also induced tumor-specific immune responses in peripheral blood T cells of all 6 evaluable patients in an in vitro immune response assay.
Thus, early data suggest that the combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is likely safe and effective in generating systemic antitumor immune responses and systemic tumor shrinkage.
Citation Format: Tanaya Shree, Michael S. Khodadoust, Debra Czerwinski, Matthew J. Frank, Wan X. Hong, Rachel Greenstein, Summer Guo, Steven Long, Brock A. Martin, Ronald Levy. Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT133.