CAR T-Cell Therapy for Multiple Myeloma (MM)

Introduction: Multiple myeloma (MM) is an incurable haematological malignancy characterised by clonal expansion of abnormal plasma cells in the bone marrow. MM affects around 384 people in Ireland each year, and the median age of diagnosis is 65 years. A diagnosis of MM is indicated by greater than 10% plasma cells in the bone marrow, and evidence of end-organ damage (hypercalcemia, renal insufficiency, anaemia and bone lesions). Typical treatment of MM comprises a combination of several drug classes, normally three or four, including proteasome inhibitors, immunomodulatory agents, monoclonal antibodies, alkylating agents and corticosteroids. Treatment aims to get the patient into deep remission, to achieve the best chance of progression free survival, as eventually all patients will relapse.

The current standard-of-care treatment approach is to treat MM continuously to maximise treatment response and achieve deeper remission, both at diagnosis and relapse. As a result, patients require many hospital visits, may experience continuous side effects, and additionally this has financial implications. Chimeric antigen receptor (CAR) T-cell therapy has changed this treatment paradigm approach. CAR T-cell therapy is administered as a single treatment and provided a patient responds, does not require continuous maintenance therapy. CAR T-cell therapy has emerged in recent years as a promising treatment strategy for many blood cancers. CARs are genetically engineered T-cell receptors designed to target a tumour-associated antigen and promote T-cell mediated death. CAR T-cell therapy is currently FDA approved for both early and later stages of MM.

CAR T-Cell Process

Currently available CAR T-cell therapies are manufactured specifically for each individual patient (Figure 1). The patient undergoes leukapheresis, a process where white blood cells are separated from blood in order to isolate T-cells. In a laboratory, these T-cells are genetically modified to express a CAR targeting the desired tumour-associated antigen. CARs are hybrid molecules that contain both an antigen recognition domain and T-cell activation domain. The new CAR T-cells are then stimulated to expand ex-vivo using growth factors until there are enough to proceed with infusion back into the patient. This manufacturing process can take 6 weeks, and so the patient receives bridging therapy in the meantime. Once infused, the CAR T-cells continue to expand within the patient’s bloodstream, bind to malignant cells and orchestrate recruitment of immune cells to kill the malignant cells.

CAR-T Targets

To ensure optimal efficacy, CAR-T target antigens should be highly expressed on malignant cells, with little to no expression on non-malignant cells. There are currently two CAR T-cell therapies approved for MM, ide-cel and cilta-cel, which both target B-cell maturation antigen (BCMA). BCMA is highly expressed on MM cells, and its expression remains high even at relapse and in patients with high-risk extramedullary disease. Importantly, BCMA is not expressed on haematopoietic stem cells or non-haematological cells making it an ideal target. CAR T-cell therapy targeting BCMA has improved outcome for both standard-risk and high-risk patients, however high-risk patients still relapse in a shorter amount of time. Other targets under investigation include GPRC5D and SLAMF7 which are both highly expressed on the surface of MM cells. Therapies targeting both are in early phase clinical trials and have shown promising results in the relapsed/refractory settings.

Challenges

Unfortunately, there are toxicities associated with CAR T-cell therapy. The most common is cytokine release syndrome (CRS) which is a systemic inflammatory response where high levels of cytokines are released from immune cells into the bloodstream. This can be characterised by nausea, fever and multiple organ failure. Many patients will experience low-grade CRS which is tolerable, but those who experience high-grade CRS may need clinical intervention. Another complication associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). This is a neurological toxicity thought to be a manifestation of CRS. Presentation can range from loss of cognitive function to seizures and cerebral oedema.

Like all therapies for MM, a huge clinical challenge is patients developing resistance. There are many factors that impact drug resistance, all ultimately resulting in selection of a subclonal population of resistant cells. For example, BCMA-directed therapy will target cells expressing BCMA, but a small proportion of malignant cells without BCMA will survive and eventually expand resulting in clonal evolution. This new clonal population of cells will not respond to the therapy leading to relapse. As a result research is continuously searching for novel CAR-T targets for potential use in later disease stages.

There are also several logistical challenges associated with CAR T-cell therapy. Firstly, the manufacturing process is lengthy and in some cases may not be successful due to factors such as low white blood cell count in the sample or effects of medication. Additionally, this therapy is significantly costly. In the UK, the cost is reported as £280,000 (around ¤337,500) per patient.

Conclusion

CAR T-cell therapy is a promising treatment approach for MM and will undoubtedly change the future treatment paradigm. However, patients with high-risk features still ultimately have the worst outcome, and therefore should still remain the focus of future novel therapies. There are several clinical and logistical challenges for CAR T-cell therapy, but as research continues hopefully these will be minimised.

References available on request

Written by Roisin McAvera, Senior Postdoctoral Researcher, Royal College of Surgeons in Ireland

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