Adoptive cell therapy in multiple Myeloma

ABSTRACT

Introduction: Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re-infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen-specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells).

Areas covered: This review article summarizes our up-to-date knowledge on ACT in MM, its promises, and upcoming strategies to both overcome its toxicity and to integrate it into future treatment paradigms.

Expert opinion: Early results of clinical studies using CAR T cells or TCR- engineered T cells in relapsed and refractory MM are particularly exciting, indicating the potential of long-term disease control or even cure. Despite several caveats including toxicity, costs and restricted availability in particular, these forms of immunotherapy are likely to once more revolutionize MM therapy.

KEYWORDS:

• Multiple myeloma
• adoptive cell therapy
• marrow infiltrating lymphocytes (MILs)
• chimeric antigen receptor (CAR) cells
• TCR- engineered T cells
• dendritic cells (DCs)
• tumor associated antigens (TAAs)
• antigen presenting cells (APC)

Article highlights

• adoptive cell transfer (ACT) is a potentially curative form of immunotherapy

• promising forms of ACT include the use of non-engineered (DILs, MILs, gammadelta T cells) and genetically engineered effector cells (CAR T and NK cells, TCR- engineered T cells)

• methods to introduce CAR constructs include viral infection, as well as transposon- based systems (Sleeping Beauty), and RNA transfection

• CTL019 provided the first evidence that CAR T cells represent a potential novel therapeutic approach in MM

• CAR T cells directed against BCMA have provided the most impressive results in MM until today

• first preclinical data on the use of allogeneic BCMA-CAR T cells are promising

• future CAR and genetically-engineered TCR cells may be more personalized to target neo-antigens

• suicide genes, safety domains, gene editing and the introduction of dual- targeting CARs may improve CAR cell safety, persistence and efficacy

• initial data on TCR- engineered T cells against NY-ESO-1 warrant further investigations

• several clinical studies to test the combination of ACT with other forms of immunotherapy (immune checkpoint inhibitors, IMiDs) as well as conventional and novel MM therapies are ongoing

This box summarizes key points contained in the article.

Declaration of Interest

K Podar is a consultant for Amgen and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.