Marrow Infiltrating Lymphocytes and Vaccines in Myeloma

Despite several decades of research with limited clinical successes, immunotherapy is now establishing a permanent presence in the clinical arena for several malignancies including multiple myeloma. The ability to understand the mechanisms mediating tumor-induced tolerance as well as the availability of reagents to target them have facilitated the clinical development of several immune-based strategies. The efficacy of adoptive cell therapies has already been demonstrated by the clinical benefit observed with allogeneic bone marrow transplantation where the immune-mediated graft vs. tumor effect accounts for the deeper and more durable clinical responses when compared to autologous stem cell transplantation. Recently, adoptive T cell approaches have focused on ex vivo manipulation of cells with the goal of increasing their tumor specificity. To date, the approaches can be divided into three groups: unmodified cells; T cells expressing transgenic T cell receptors; and cells modified with chimeric antigen receptors (CARs). Each has its own benefits. Historically, adoptive T cell therapy utilized peripheral blood lymphocytes in large part because of their ease of access. Early studies in myeloma demonstrated their ability to augment immune reconstitution and effectively transfer vaccine-specific responses. However, their lack of tumor specificity has prompted our group to evaluate the role of marrow infiltrating lymphocytes (MILs). These cells possess a broad endogenous tumor specificity and are enriched for central memory T cells that make them a more suitable source of cells for adoptive T cell approaches. The properties and potential benefits of this approach will be discussed.

Another immunotherapeutic approach with potential appeal is the use of myeloma vaccines to address the issue of minimal residual disease. In light of the fact that patients with myeloma rarely have long-term sustained remissions, it is reasonable to integrate a novel approach that is capable of eradicating the remaining disease burden by generating a broad, myeloma-specific, systemic immune response. We have developed a cellular, GM-CSF-based, myeloma vaccine which has been administered in the combination with the immunomodulatory agent, lenalidomide, to patients in a near complete remission (negative M-spike but with a positive immunofixation). We have demonstrated priming of a tumor-specific immune response which correlates with a durable clinical benefit.

With the ever-increasing development of immune-based approaches, combining them with various agents in different disease setting to improve the overall outcomes of myeloma patients.