Oncolytic Reovirus Immune Priming: A Phase 1b Study of Reolysin with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Background: While novel agents have improved the outcome for multiple myeloma (MM), the disease remains incurable. Our preclinical work has shown that MM cells from relapsed/refractory patients are very sensitive to the combination of Reolysin (a proprietary formulation of an oncolytic reovirus) and bortezomib (BZ), resulting in synergistic levels of endoplasmic reticulum (ER) stress. A pilot phase 1 study showed that Reolysin was well tolerated in relapsed/refractory MM patients and was associated with prolonged stable disease. Methods: Relapsed/refractory MM patients including patients refractory to BZ were included. This is a phase 1b study of 3 escalating doses of Reolysin (cohort 1; 3 x1010 TCID50, cohort 2; 4.5 x1010 TCID50, and cohort 3; 9 x1010 TCID50). Reolysin is given on days 1, 2, 8, 9, 15, and 16. Patients receive 40 mg dexamethasone and 1.5 mg/m2bortezomib on days 1, 8, and 15. Cycles are repeated every 28 days in the absence of disease progression or unacceptable toxicity. Results: Eight patients have been enrolled, seven were male and the median age was 55 (range, 33 - 66). The median number of prior therapies was 4 (range 1 to 6). All patients were previously exposed to BZ, and 6 patients were previously exposed to both an immunomodulatory agent and carfilzomib. Most patients had ISS stage I disease at study entry (n=5), 2 had stage II and 1 had stage III. The combination was well tolerated and most treatment-related toxicities were transient and easily managed with supportive care. The most common treatment-related toxicities were grade 1 diarrhea (n=4), grade 1 fatigue (n=4), grade 1 flu-like symptoms (n=5) and grade 1 headache (n=4). No dose limiting toxicities occurred in cohort 1 or 2. Three patients completed 1 cycle of treatment only, 2 completed 3 cycles, and 1 patient completed 4 cycles. One patient remains on treatment. Reasons for treatment discontinuation included disease progression (n=4), clinical deterioration (n=1) and patient withdrawal (n=2). Six patients were evaluable for response, 3 patients had stable disease lasting at least 3 cycles whereas 3 patients had progressive disease at the end of cycle 1. Ex vivo treatment of primary MM cells and MM cell lines (U266 and RPMI-8226) with Reolysin revealed a dramatic induction of PD-L1 expression as measured by qRT-PCR and flow cytometry. Furthermore, ex vivo treatment of MM patient mononuclear cells with Reolysin resulted in NK and T cell activation. These results suggest that the addition of an anti-PD-1 or anti-PD-L1 agent may augment the anti-MM activity of Reolysin. Conclusions: The combination of Reolysin, BZ and dexamethasone is well tolerated in a heavily pretreated MM patient population. Cohort 3 is currently enrolling at the 9 x1010 TCID50 dose level of Reolysin. The potential anti-MM effects of immune activation following Reolysin infusion may be mitigated by MM expression of PD-L1. Additional cohorts exploring the tolerability, efficacy and pharmacodynamics of the combination of Reolysin, BZ or carfilzomib, dexamethasone and an immune checkpoint inhibitor will be added following completion of cohort 3. Disclosures Kelly: Pharmacyclics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Coffey:Oncolytics Biotech: Employment. Gill:Oncolytics Biotech: Employment.

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway

“…There is also an ongoing phase 1b trial of Reolysin combined with Bortezomib and dexamethasone in RRMM (NCT02514382). Preliminary results for six patients showed stable disease in three patients and progressive disease in three patients [ 91 ]. Kelly et al showed that Reolysin triggers a significant transient upregulation of PD-L1 in MM cell lines and in vivo, which could have mitigated treatment response in the clinical trial.…”

Oncolytic Reovirus and Immune Checkpoint Inhibition as a Novel Immunotherapeutic Strategy for Breast Cancer

“…Further, non-malignant cells lines have been shown to be non-permissive to RV-mediated oncolysis in vitro [ 10 , 11 ]. Additionally, RV has been shown by both our group and others to have extensive preclinical and clinical efficacy against a number of cancer histologies [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ], underscored by the establishment of a potent anti-tumor immune response. Furthermore, a randomized phase II clinical trial of RV + paclitaxel in metastatic BrCa has been completed by the Canadian Clinical Trial Group (CCTG).…”

Oncolytic virotherapy as an immunotherapeutic strategy for multiple myeloma

“…There are two more active clinical trials currently utilizing RV in MM; NCT03015922, in which Reolysin is being tested in combination with the immunomodulatory drug lenalidomide or pomalidomide, and NCT02514382, utilizing Reolysin with bortezomib and dexamethasone. Interim results have demonstrated that while safe, treatment results in stable disease in only half of evaluable patients (n = 3) 96 . One strategy to improve RV as a therapeutic agent for MM would be to combine it with a histone deacetylase inhibitor(HDAC-i).…”

“…Impetus for this combinatorial treatment approach comes in part from the ongoing phase I clinical trial utilizing RV in MM (NCT02514382) conducted by Kelly and colleagues 96 . During interim analysis, they found that ex-vivo treatment of patient tumour samples led to a significant increase in MM cell expression of PD-L1, as measured by flow cytometry and RT-PCR 96 .…”

“…Impetus for this combinatorial treatment approach comes in part from the ongoing phase I clinical trial utilizing RV in MM (NCT02514382) conducted by Kelly and colleagues 96 . During interim analysis, they found that ex-vivo treatment of patient tumour samples led to a significant increase in MM cell expression of PD-L1, as measured by flow cytometry and RT-PCR 96 . Subsequent in vivo experiments by this group using the 5TGM1-luc murine model have shown that treatment with both Reolysin and a PD-L1 inhibitor lead to a decrease in disease burden, as well as a significant increase in overall survival compared to either monotherapy alone 116 .…”