COMMENTARY

Cellular Immunotherapy for Multiple Myeloma Advancing Rapidly

Theodore Bosworth

Disclosures

January 30, 2017

In This Article

CAR T Cells

The evidence of efficacy from anti-CD19 CARs in MM, another cellular immunotherapy advancing rapidly, is counterintuitive. According to Dr Stadtmauer, CD19 is not commonly expressed on MM plasma cells. However, interest in this approach has gained momentum when a highly pretreated patient achieved a CR on this therapy after SCT.[3] In new data from a pilot study presented at the ASH annual meeting,[4] progression-free survival (PFS) following anti-CD19 CAR and a salvage SCT met or exceeded PFS typically observed after first-line SCT in 3 of 10 study participants. Historically, disease control following salvage SCT has been far less.

"The correlation of PFS with the CAR T-cell frequency in the bone marrow and prolonged PFS in 3 subjects is suggestive of clinical efficacy," reported Alfred L. Garfall, MD, an assistant professor of medicine at the Perelman School of Medicine at the Hospital of the University of Pennsylvania. The first author of this report and a colleague of Dr Stadtmauer, Dr Garfall suggested that the activity of anti-CD19 CARs in MM may be related to the presence of myeloma cells that exhibit a B-cell phenotype. Although the MM plasma-cell populations were negative for CD19 by flow cytometry in all nine evaluable patients, subsequent analyses revealed small proportions of CD19+ MM plasma cells (≤1.5%) in seven of the patients.

Anti-CD19 CARs have demonstrated dramatic responses in a variety of B-cell malignancies, but there are other types of CARs being explored in MM. At the ASH annual meeting, data were presented on B-cell maturation antigen (BMCA)-specific CARs in a phase 1 study.[5] In this study, which was led by Adam D. Cohen, MD, of the Abramson Cancer Center at the University of Pennsylvania but included both Drs Stadtmauer and Garfall as coinvestigators, data were available for six patients. All had MM cells with BMCA expression.

There has been one ongoing CR with minimal residual disease –negative bone marrow and a very good partial response. Two other patients had modest CAR T-cell expansion with a transient minimal response. Although five of the six patients developed cytokine release syndrome (CRS), these were manageable with supportive care and, in some cases, tocilizumab. There were grade 4 toxicities, including one case of posterior reversible encephalopathy syndrome, but both the promising responses and the largely manageable toxicity are encouraging for further study. The correlation of depth of response with degree of CAR T-cell BMCA expression has been reassuring, according to Dr Cohen.

There were no new data on enhancing the affinity of T cells for MM by transducing them with T-cell receptors (TCR) specific for myeloma cell surface antigens, but Dr Stadtmauer indicated that this is not because this approach is any less promising. He described work with TCRs against NY-ESO-1 and MAGE-A3, but he reported that other antigen targets are being pursued. The true potential of TCRs, like MILs and CAR T cells, may be achieved in treatment strategies that combine these approaches with additional strategies, such as myeloma cell–targeted vaccines.

"There is a strong rationale for combining immunotherapy approaches, especially those that combine antigen-specific approaches," Dr Stadtmauer said. This not only includes combining adoptive cell transfer strategies with vaccines but also combining vaccines with drugs that inhibit other components of the bone marrow microenvironment, such as checkpoint proteins, that sustain neoplastic plasma cells. As more of these components are isolated, the strategies for combinations have proliferated.

The "multitude of clinical trials evaluating these approaches is encouraging," according to Dr Stadtmauer. Some of the principles of the current strategies have been in experimental testing for years, but the growing body of encouraging clinical data demonstrates an ongoing transition from theory to new opportunities to alter the prognosis of advanced MM.

Dr Stadtmauer reports financial relationships with Amgen, Celgene, Janssen, Novartis, and Takeda.
Dr Garfall reports financial relationships with BioInvent, Medimmune, and Novartis.
Dr Borrello reports financial relationships with Bristol-Myers Squibb, Celgene, and WindMIL Therapeutics.
Dr Cohen reports financial relationships with Bristol-Myers Squibb and Janssen.

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