Chimeric Antigen Receptor (CAR) therapy for multiple myeloma

Abstract

SummaryThe introduction of chimeric antigen receptor (CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma (MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells. This might be related to the fact that an ideal surface target has not yet been identified or the presence of strong local immunosuppression in the tumour microenvironment, which is a hallmark of MM. In this review, we provide a comprehensive overview of promising target molecules for CAR T cell approaches in MM and we outline a number of ways in which the local immunosuppression in MM can be overcome. By providing a strategy for the design of CAR T cell treatments for MM we hope to transform this new therapeutic approach into a valuable tool within the therapeutic armamentarium for MM.Keywords: chimeric antigen receptors, multiple myeloma, immunotherapy, tumour immunology.Multiple Myeloma (MM) is an incurable plasma cell (PC) malignancy, which develops in the bone marrow (BM) and eventually causes renal failure, immunosuppression with repeated infections, anaemia and bone lesions (Palumbo & Anderson, 2011). There have been significant therapeutic advances over the past decade and the median survival of MM patients has increased to approximately 6 years (Kumar et al, 2014). However, most patients will still eventually suffer a fatal relapse after an initially effective therapy. This is due to the persistence of chemotherapy-resistant PC clones (Chaidos et al, 2013) in the BM even after destruction of the bulk of tumour cells (Rawstron et al, 2013) and, accordingly, the disease will become more and more refractory to chemotherapy after each additional line of treatment.Multiple Myeloma cells primarily localize to the BM and remain readily accessible to immune effector cells (Raab et al, 2009). However, as the disease progresses, the adaptive immune system will become more and more paralysed, resulting in severely compromised B cell and T cell responses (Villunger et al, 1997;Schutt et al, 2006). As MM itself is dependent on the suppression of the adaptive immune response, the development of immunotherapeutic approaches correcting this dysfunction seems an attractive option for MM patients. Allogeneic stem cell transplantation (alloSCT) is one of the most promising ways of restoring the immune system's ability to recognize and destroy MM cells and is currently, in addition to the intensive Total Therapy protocols introduced by the Arkansas group (Barlogie et al, 2014), the only potentially curative approach for MM patients (Lokhorst et al, 2010). However, this therapeutic modality has been severely hampered by its high treatment-related morbidity and mortality (Lokhorst et al, 2010), resulting predominantly from graft-versus-host disease (GvHD) (Vekemans et al, 2014). Therefore, more speci...

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…5,6,19,23 Inclusion of costimulatory domains in CARs has been a critical step in the development of CAR-T therapies. 6,7,[26][27][28] First-generation CARs contained the primary activating signaling molecule CD3z, which was sufficient to activate a T-cell response, 6,19,22 yet, the signal elicited was weak, leading to the creation of secondgeneration CARs, which added a second costimulatory signal. [6][7][8] The addition of CD28, 4-1BB, OX40, and immune T-cell costimulator led to more robust cytokine production and enhanced cytolytic capacity of CAR-Ts.…”

“…5,6 CAR design and T-cell culture methods continue to undergo iterations to optimize the many factors that determine patient outcomes after infusions of CAR-Ts. 18,24,26,41 …”

“…82 CD138 expression is found on epithelial cells of organs such as salivary glands, liver, and skin; an antibody-drug conjugate targeting CD138 was associated with dose-limiting toxicities including elevated liver enzymes and palmar-plantar erythrodysesthesia in a small number of patients. 20,26,[81][82][83] Five patients with relapsed and refractory MM or plasma cell leukemia were treated on a phase 1 clinical trial of anti-CD138 CAR-Ts. 36 All patients had CD138 1 MM present in their bone marrow.…”

Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality?

“…65 Alternatively, engineered T cells are being explored as immunotherapy for hematologic malignancies, including MM. 66,67 Chimeric antigen receptor (CAR) T cells involve the incorporation of an antibody variable chain and positive costimulatory molecule into the T-cell z receptor such that engagement with the antigenic target provokes T-cell-mediated killing. A potential concern is that ligation of PD-1 on the CAR T cell will induce anergy.…”

Towards Stratified Medicine in Plasma Cell Myeloma

“…These were tested as monotherapy on relapsed/refractory myeloma. Antibodies to other antigens such as CD319 (elotuzumab) and CD138 (BT-062) have shown less impressive results but may still be effective as part of combination therapy for treating MGUS or earlier stage PCM [48,96]. Other markers with potential as mAb targets include CD74 (milatuzumab), CD54, CXCR4, B cell-activating factor (BAFF) and interleukin-6 (IL-6) [58,96].…”