An Allogeneic GM-CSF-Based Vaccine in Combination with Lenalidomide Induces Durable Remissions and Sustained Immunological Responses in Multiple Myeloma

Introduction:

Novel therapies have significantly increased the complete response (CR) rates in multiple myeloma (MM) with corresponding improvement in progression free survival (PFS). However, the emergence of treatment resistant sub-clones leads to disease relapse in a significant number of patients. Despite continuous improvements, cancer vaccination strategies have not been effective in preventing disease progression. Possible reasons include suboptimal timing of administration, antigen selection, disease burden at the time of vaccination and lack of the appropriate adjuvant. Here, we present the results of a phase I/II trial evaluating an allogeneic MM cellular vaccine administered in the context of a minimal disease burden in combination with lenalidomide (Len) to prevent MM progression.

Methods:

The vaccine consists of two MM cell lines (U266 and H929) coupled to a GM-CSF producing leukemia cell line (K562, GVAX® platform). After irradiation, the vaccine was cryopreserved until further use. Patients achieving a near CR (nCR), defined as absent M-spike and positive urine/serum immunofixation, were observed for at least 4 months to monitor response stability before enrollment. Vaccination was administered at 1, 2, 3 and 6 months together with the PrevnarÒvaccine in patients continuing on Len maintenance. Bone marrow (BM) and peripheral blood (PB) samples were utilized for immune monitoring, T-cell receptor (TCR) sequencing, and B-cell receptor (BCR) sequencing for minimal residual disease (MRD) determination using the immunoSEQ^®Assay (Adaptive Biotechnologies, Seattle, WA)at enrollment, 3 months, 1 year and long-term follow-up timepoints.

Results:

Of the 30 patients that were initially observed, 15 patients maintained a stable nCR for at least 4 months and were vaccinated at the established timepoints. Patients who either progressed or improved their clinical response transitioning to a CR were not considered eligible. TCR immunoSEQ analysis revealed both the appearance and expansion of new T-cell clones without overall changes in repertoire clonality, suggesting active response to vaccination in both BM and PB compartments. Persistence of expanded clones was detected by immunoSEQ up to 1 year after the first vaccine dose in all patients. Phenotypic analyses and antigen-stimulation assays on BM T cells demonstrated maintenance of MM-specific T-cell reactivity at all examined timepoints. Polyfunctional MM-specific T-cell responses were detected in follow-up samples up to 8 years after the first vaccine dose and surprisingly showed persistence of MM-specific T-cell immunity when compared to the 1-year time point. Although negative MRD status and depth of response directly correlated with disease remission, some patients developed a low, but persistent MRD and M-spike (<0.5 g/dL) without actually meeting criteria for disease recurrence. These findings suggest that while vaccination can further reduce the disease burden in some patients, the development of persistent immune equilibrium with vaccination is important for disease control. Strikingly, with a median follow-up time of 4.73 (range 2.9-7.25) years, the vaccine group (n=15) did not reach the median PFS (mPFS) with an overall PFS at 6 years of 75%, which is significantly higher than the mPFS of patients not enrolled due to achievement of CR (n=5, mPFS = 2.1 years, p<0.01).

Conclusions:

These data demonstrate that an allogeneic MM vaccine effectively stimulates antitumor immunity in the setting of low disease burden with Len. Moreover, polyfunctional antitumor immune responses were persistent up to 8 years post vaccination. It is likely that the diversity of antigens in the vaccine supported polyclonal MM-specific immune responses, thus establishing long-term MM control. Although depth of response to treatment is a critical factor in maintaining MM remission, the long-term persistence of functional MM-specific T-cell clones highlights the importance of an active immune response to prevent MM relapse. Overall, these findings suggest that allogeneic MM vaccination could be an integrative therapy to support persistent antitumor immunity and increase PFS, especially in patients who responded to treatment without achieving an MRD-negative status.