Immunotherapy

Monoclonal antibodies

that target specific cell surface proteins or antigens are expected to show meaningful advancement over the next few years. Outcomes associated with the recently approved mAbs, daratumomab (targeting cell surface protein CD38) and elotuzomab (targeting SLAMF7), in relapsed refractory multiple myeloma patients have demonstrated improving outcomes. There are many mAbs under investigation targeting a wide range of antigens (including CD38, CD138, IL6, BAFF, RANKL, DKK1, PD-1).

Bispecific monoclonal antibodies

– BiTES have emerged as a promising therapeutic approach for acute lymphoblastic leukaemia and some types of lymphoma and is being investigated in vitro and in vivo in multiple myeloma.

Therapeutic vaccines

Cancer vaccines that treat cancer are still uncommon, but many are being studied in clinical trials and it is a promising area of ongoing research. The vaccines with which people are familiar are those against infectious disease which are administered to healthy individuals with a functioning immune system. They work by priming the immune system to respond to an antigen associated with a specific pathogen, so that when the system encounters the infection it already knows how to fight it. Cancer vaccines are administered in the presence of existing cancer and a dysfunctional immune system. The approach to vaccine therapy against cancer is to ensure the vaccine is equipped with the right antigen that might encourage an immune response to a tumour which is already present, but which the immune system has failed to respond to.

Immune checkpoint inhibitors

are a specific type of cancer drug that allows the immune system to destroy cancer cells and are promising agents that control anti-tumour immune responses. In multiple myeloma clinical trials (targeting the PD-1 and PD-L1 axis) are being conducted in combinations with the other drugs.

T cell approaches

include Chimeric antigen receptor (CAR) T cells targeting various cell surface antigens, Marrow-infiltrating lymphocytes and donor derived T cells via allogenic transplant. In MM, the efficacy of immunotherapy is based on the observation that (allogenic) stem cell transplantation is curative for a subset of patients due to the donor derived immune response to recipient myeloma cells – the graft-versus-myeloma effect. As this is primarily medicated by allogenic T-cells it makes T-cells an interesting area of research.

• CAR T-cells – The genetic modification of autologous T cells with chimeron antigen receptors (CARs) represents a breakthrough for gene engineering as a cancer therapy for hematologic malignancies. The patient’s T-cells are harvested and then engineered in a lab to be able to identify specific markers on myeloma cells (eg. CD19, CD38, BCMA, Kappa light chains, etc). These engineered T-cells are then stimulated in the lab to make them more active and to proliferate and grow. Infused myeloma-directed T-cells then directly kill myeloma cells and stimulate T-cell immunity. CAR T cells targeting CD19 have been the most successful and most studied to date. CD19 is a surface protein on B cells and is therefore a target for studies in relation to acute lymphoblastic leukaemia and non-Hodgkin lymphoma though CD19 is not routinely expressed on the surface of clonal plasma (which includes myeloma) cells. BCMA is therefore a preferred target for CAR T-cells in MM as it is highly expressed on the surface of such cells.
• B cell maturation antigen (BCMA) – BCMA is an antigen that plays a key role in the regulation and differentiation of B cells into plasma cells. BCMA is expressed homogeneously on the surface of plasma cells in patients with MM, plasma cell leukaemia and plasmacytomas. BCMA which has shown considerable promise in early laboratory research. A mAb that effectively targets BCMA has yet to be discovered. With recent successes of daratumumab, CAR-CD38 T cells are now in clinical trials. Going forward, donor derived T cells may be a promising avenue, combining the concept of targeted therapy and allogenic SCT. Future studies are likely to focus widely on determining the best drug combinations.
• Marrow-infiltrating lymphocytes (MILS) – an emerging area of therapeutic T cell intervention has been the utilisation of marrow-infiltrating lymphocytes, a novel from of adoptive T-cell therapy. Some research conclusions suggested a lack of tumour specificity with respect to CAR-T cells and therefore promoted interest and research in the evaluation of MILs. The hypothesis is that as such cells are enriched for central memory T cells, that potentially makes them a more suitable source of cells for adoptive T cell approaches.