The field of multiple myeloma (MM) has seen significant therapeutic advances over the last decade including the recent advent of Chimeric Antigen Receptor T cell (CAR-T) therapy. Currently there are two FDA approved CAR-T products for MM, both targeting B cell maturation antigen (BCMA). These agents have demonstrated striking therapeutic efficacy in patients with advanced disease and are now also approved in earlier relapse. CAR-T therapy is associated with unique toxicities including cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, risk of infections and cytopenias. While response rates are dramatic, most patients ultimately experience disease progression due to therapeutic resistance potentially arising from lack of persistence and exhaustion of CAR-T cells, emergence of antigen negative variants, and the immunosuppressive tumor microenvironment. Significant efforts in the field are dedicated towards improving the efficacy and mitigating the toxicity of CAR-T cell therapy. In this publication, we review the approved and investigational CAR-T models for MM.

Immunotherapy, including immune checkpoint blockade, CART cells and bispecific antibodies have resulted in dramatic improvements in outcomes for patients with hematological malignancies, demonstrating the unique potency of the immune system in targeting malignant cells. The development of cancer vaccines aims to evoke an activated effector cell population and a memory response to provide long term immune surveillance to protect from relapse. Developing a potent cancer vaccine relies on identifying appropriate antigen targets, enhancing antigen presentation, and overcoming the immune suppressive milieu of the micro-environment. Critical advances include the identification of neoantigens as targets for high affinity T cells, multi-antigenic targets via whole-cell or multi-peptide platforms, dendritic cell-based strategies, and adjunct immunoregulatory agents to enhance response. In the present review, we examine the current understanding of immune dysregulation in hematologic malignancies, the rationale for cancer vaccines, and the clinical and immunologic response data available from preclinical and clinical settings.

Multiple myeloma (MM) is a malignant disease in which clonal plasma cells proliferate abnormally. In patients with MM, the number and function of NK cells are suppressed, resulting in reduced immune surveillance and clearance of myeloma cells. Restoring or enhancing the killing effect of NK cells on myeloma cells is an important strategy for MM immunotherapy. At present, a series of great progress has been made in preclinical and clinical studies for NK cell adoptive therapy and CAR-NK therapy. This article introduces the current status of various treatment strategies for MM, NK cells in MM, and reviews the latest results of NK cell immunotherapy for MM.

Plasma cell myeloma (multiple myeloma) is a blood cancer characterized by the clonal proliferation of plasma cells in the bone marrow. Treatment strategies evolve year by year, new drugs getting Food and Drug Administration (FDA)-approved each year. Chimeric antigen receptor (CAR) therapies are an advanced form of immunotherapy that engineer T cells to recognize and destroy cancer cells. In recent years, adoptive cellular therapies have been successfully used to treat relapsed or refractory patients. Now, growing evidence supports their effectiveness when used earlier in treatment, even as an alternative to autologous hematopoietic stem cell transplantation. Ongoing research is expanding CAR therapy to solid tumors and enhancing safety and efficacy through innovative designs and combination strategies. In this paper, we aim to highlight the brief history and the latest advancements in CAR T-cell and NK-cell therapies for plasma cell myeloma.

With upfront use of triplet- and quadruplet-based regimens coupled with autologous stem cell transplant (ASCT) and maintenance lenalidomide, a high proportion of multiple myeloma (MM) patients are achieving deep and durable responses. Yet, myeloma invariably relapses, with refractoriness to one or more drugs at first relapse. This therapeutic gap has been partially filled by T-cell engager (TCE) therapies that have demonstrated remarkable response rates and prolonged remissions in heavily pretreated patients with MM, providing off-the-shelf immunotherapy options leading to the U.S. Food and Drug Administration (FDA) approval of three bispecific TCEs teclistamab, elranatamab, and talquetamab. We review the most salient aspects of TCE design and clinical experience in MM treatment. Combination approaches overcome resistance mechanisms, while earlier TCE use could enhance depth and durability of response. Outpatient step-up dosing (SUD) further enables community adoption.

Precursor plasma cell disorders include monoclonal gammopathy of undermined significance (MGUS) and smoldering multiple myeloma (SMM). These conditions carry a variable risk of progression to symptomatic myeloma and there are ongoing efforts to improve risk stratification to identify patients that are at highest risk of progression. Advanced imaging plays a crucial role in diagnosis and monitoring, and more sensitive tools to measure serum monoclonal proteins and circulating tumor cells are being developed. The data for early intervention in SMM continues to evolve, with several phase III studies demonstrating benefit compared to observation. There are ongoing studies evaluating the role of combination and T cell immunotherapies in patients with precursor plasma cell disorders. This review will highlight the current state of the art tools in diagnosis, risk stratification, and data for early interception in patients with precursor plasma cell dyscrasias.

Lymphomas are a group of malignant proliferations of B, T or NK-lymphoid cells at different stages of maturation. While they primarily occur in lymph nodes or lymphatic tissues, they can also involve bone marrow, blood, or other organs. Despite advances in treatment, many patients experience relapse, or develop refractory disease, prompting the development of new therapies. One of the most promising innovations is represented by chimeric antigen receptors (CAR) T-cell therapy, that works by genetically modifying a patient's T lymphocytes to better target and kill their cancer cells. Currently, all FDA-approved CAR T-cell therapies target CD19 (a surface protein expressed on B lymphocytes), however, ongoing research includes CAR-Ts that address novel targets or target multiple antigens. This study aims to provide a comprehensive overview on the clinical use and therapeutic efficacy of both approved and emerging CAR-Ts in the treatment of lymphoma.

Adoptive cellular therapy, or the collection and transfer of immune cells to patients, is emerging as a treatment option for many malignancies, especially hematologic malignancies, with a growing role in solid tumors and non-malignant conditions such as autoimmune diseases. The adoptive transfer of the innate immune cell natural killer (NK) cells is uniquely poised as a potential therapy alone or as an adjunct to other immune-targeted therapies for patients with cancer, with several advantages over other cell therapies such as T cells. We review key concepts in NK cells as a therapy for human disease and discuss key trials using NK cells in malignancy.

Chimeric antigen receptor (CAR)-T cell therapy has proven to be a revolutionizing immunotherapeutic strategy for treating relapsed or refractory lymphoma, achieving remarkable clinical responses. However, there remain some challenges including treatment resistance and early relapse in a minor proportion of patients. The lymphoma tumor microenvironment (TME) is a heterogeneous and dynamic milieu composed of lymphoma cells, immune cells, stromal components, cytokines, and extracellular matrix proteins. CAR-T cell infusion alters the composition of TME and thus impact the endogenous immune response. Additionally, various components of the TME affect the persistence, activity and cytotoxicity of CAR-T cells, which is a key endogenous factor that impeding the efficacy of CAR-T cell therapy in lymphoma. Herein, we review the role of lymphoma TME on CAR-T cells, and discuss strategies targeting TME components to overcome resistance and improve the effectiveness of CAR-T cells.

Chimeric antigen receptor T (CAR-T) cell therapy, a type of precision immunotherapy, has shown promising outcomes in treating certain types of cancers, although limited by the antigen escape, suppression on the tumor microenvironment (TME), and CAR-T cell depletion. Molecularly targeted drugs can enhance the anti-cancer efficacy by targeting key signal transductions against cancers, providing a clue for optimizing the CAR-T cell therapy. Moreover, molecularly targeted drugs synergistically assist CAR-T cells to transform the TME, boost anti-cancer activities and inhibit immune escape. Their combination has rushed into the spotlight of research on individualized treatments for multiple myeloma (MM). In the present review, we described frequently used molecularly targeted drugs in the combination of CAR-T cell therapy against MM.

Chimeric antigen receptor-natural-killer (CAR-NK)-cells are a promising cancer cell therapy. Several features of CAR-NK-cells are suggesting an advantage over CAR-T-cells such as less complex manufacturing, "off-the-shelf" use and lower risks of cytokine release (CRS) and immune effector cell-associated neurotoxicity syndromes (ICANS). CAR-NK-cells derived from several sources are associated with promising pre-clinical and clinical results in haematological cancers. We comprehensively discuss the current landscape of CAR-NK-cell therapy in haematological cancers emphasizing recent progress and future directions. Additionally, we explore the biological mechanisms, engineering and sources of CAR-NK-cells. CAR-NK-cell therapy offers a safe, accessible and efficient option for haematological cancers.

Cytokines play an integral role in both promoting the efficacy of immune effector cell (IEC) therapies and in the development of the unique spectrum of associated toxicities, including CRS, ICANS, and IEC-HS. We review the various cytokines that have been employed in the IEC manufacturing process as well as the role of endogenous cytokines in promoting successful expansion and activity following cell infusion. We discuss the role of recombinant exogenous cytokines in further promoting T cell activity, as well as next-generation IEC products engineered to express cytokines that signal in an autonomous fashion. Finally, we discuss working models of several IEC-associated toxicities, highlighting the crucial role of cytokines in driving these toxicities, as well as interventions with anti-cytokine therapies to overcome them.