T cell‐based targeted immunotherapies for patients with multiple myeloma

Abstract

Despite high-dose chemotherapy followed by autologs stem-cell transplantation as well as novel therapeutic agents, multiple myeloma (MM) remains incurable. Following the general trend towards personalized therapy, targeted immunotherapy as a new approach in the therapy of MM has emerged. Better progression-free survival and overall survival after tandem autologs/ allogeneic stem cell transplantation suggest a graft versus myeloma effect strongly supporting the usefulness of immunological therapies for MM patients. How to induce a powerful antimyeloma effect is the key issue in this field. Pivotal is the definition of appropriate tumor antigen targets and effective methods for expansion of T cells with clinical activity. Besides a comprehensive list of tumor antigens for T cell-based approaches, eight promising antigens, CS1, Dickkopf-1, HM1.24, Human telomerase reverse transcriptase, MAGE-A3, New York Esophageal-1, Receptor of hyaluronic acid mediated motility and Wilms' tumor gene 1, are described in detail to provide a background for potential clinical use. Results from both closed and ongoing clinical trials are summarized in this review. On the basis of the preclinical and clinical data, we elaborate on three encouraging therapeutic options, vaccine-enhanced donor lymphocyte infusion, chimeric antigen receptors-transfected T cells as well as vaccines with multiple antigen peptides, to pave the way towards clinically significant immune responses against MM.Multiple myeloma (MM) is a fatal hematologic cancer that originates from postgerminal-center B cells.

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

“…We identified 73 different HLA ligands representing 22 of 25 (88%) previously described myeloma antigens. 42 We found 9 of the 22 detectable antigens (41%) to be exclusively presented on MM samples, 10 of 22 antigens (45.5%) to be represented both on MM and HV samples, and 3 of 22 (13.6%) exclusively presented on HV-derived samples ( Figure 3A). Of note, 7 of 9 MMexclusive antigens (77.8%) were only detectable on MCLs.…”

“…[25][26][27][28][29][30][31][32][33][34][35] However, these studies were limited in scope of antigens and HLA allotypes. 42 In our previous studies in acute myeloid leukemia and chronic lymphocytic leukemia, we demonstrated that the comprehensive and comparative analysis of the HLA-presented antigenome can identify extensive panels of broadly presented T-cell epitopes covering a multitude of HLA allotypes. 12,13 Here, we translated this systematic approach to MM.…”

“…However, broad clinical effectiveness has not yet been achieved. These previous studies were restricted to very few HLA allotypes and single antigens/epitopes, 42 limiting both the population of patients eligible for this therapeutic approach and the spectrum of inducible tumor-specific T-cell responses. Of note, recent studies demonstrated lacking degrees of tumor association for several of these tumor antigens, both on the transcriptome level 43 and importantly also on the level of HLA-restricted presentation.…”

A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma

“…Therapeutic monoclonal antibodies (mAbs) such as IPH2101 comprise just one dimension (28) of the promising, rapidly expanding field of immunotherapy for MM which also includes NK- and T-cellular therapies (29,30), vaccines (30) and immunomodulating agents, among others. Tumor-directed mAbs (31,32) as well as effector cell-targeted mAbs (21,22,33) provide an opportunity for increasing precision with which to modulate immunity against MM, as well.…”

Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

“…For example, although sclerostin null mice have high bone mineral density, they have increased B-cell apoptosis due to decreased osteoblast-derived CXCL12, resulting from increased Wnt signaling [71]. Moreover, although the immune system in general suppresses multiple myeloma [72], not all immune cells mediate this role. Regulatory T-cells and immunosuppressive myeloid-derived suppressor cells [73] are now being identified as important new targets that inhibit the immune response in multiple myeloma [74].…”