Abstract
Multiple Myeloma (MM) is a hematological cancer characterized by proliferation of malignant plasma cells in the bone marrow (BM). MM represents the second most frequent hematological malignancy, accounting 1% of all cancer and 13% of hematological tumors, with ~9,000 new cases per year. Patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic smoldering MM (SMM) usually evolve to active MM in the presence of increased tumor burden, symptoms and organ damage. Despite the role of high dose chemotherapy in combination with autologous stem cell transplantation and the introduction of new treatments, the prognosis of MM patients is still poor, and novel therapeutic approaches have been tested in the last years, including new immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies (mAbs). CD38 is a glycoprotein with ectoenzymatic functions, which is expressed on plasma cells and other lymphoid and myeloid cell populations. Since its expression is very high and uniform on myeloma cells, CD38 is a good target for novel therapeutic strategies. Among them, immunotherapy represents a promising approach. Here, we summarized recent findings regarding CD38-targeted immunotherapy of MM in pre-clinical models and clinical trials, including (i) mAbs (daratumumab and isatuximab), (ii) radioimmunotherapy, and (iii) adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38. Finally, we discussed the efficacy and possible limitations of these therapeutic approaches for MM patients.
Highlights
Reviewed by: Benjamin Bonavida, University of California, Los Angeles, United States Bipulendu Jena, University of Texas MD Anderson Cancer Center, United States Zsolt Sebestyen, University Medical Center Utrecht, Netherlands
MM arises from pre-malignant asymptomatic proliferation of plasma cells (PC), that are classified as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) [1]
This study suggested that anti-CD38 nanobodies may be effective for the modulation of CD38 enzymatic activity and for the diagnosis of CD38-expressing tumors, in patients treated with daratumumab [38]
Summary
Recent findings suggest that CD38 may represent a good target for antigen-specific adoptive cell therapy. CAR T cells specific for different MM associated antigens, such as CS1 [45], B-cell maturation antigen [46], SLAMF7 [47], and CD19 [48] proved to be effective in preclinical models and/or in clinical trials. Anti-CD38 CAR T cells displayed cytotoxic activity in vitro against either MM cell lines or primary MM cells isolated from patients. These cells may represent a powerful therapeutic tool in preclinical models of MM [49]. Anti-CD38 CAR T cells demonstrated a potent anti-tumor effect when administered intravenously or intratumorally, suggesting that these cells efficiently migrate,
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