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.

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.

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.

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.

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.

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.

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.

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.

The utilization of immune checkpoint inhibitors has fundamentally changed both the treatment landscape for a multitude of malignancies as well as our understanding of cancer biology. Despite profound advancements, the utilization of these drugs is often limited by the development of immune-related adverse events (irAEs), characterized by off-target toxicity to healthy tissue secondary to treatment. Currently, irAEs are often treated with high-dose corticosteroids, with additional immunosuppressive agents added for severe or refractory irAEs. Cytokine pathway inhibitors, particularly anti-TNFa and anti-IL-6R antibodies, are commonly used as second-line immunosuppression. The efficacy of blocking these pathways in treating irAEs, as well as their potential impact on anti-tumor response, will be discussed. Additionally, this review will also explore other cytokines implicated in irAE pathophysiology, including interleukin-17 (IL-17), interleukin-23 (IL-23), interleukin-4/13 (IL-4/IL-13) and interleukin-5 (IL-5) which play important roles in the inflammatory cascades underlying specific irAEs such as colitis, dermatitis, and eosinophilia-related toxicities.

Fields that deal with systemic autoimmune diseases such as rheumatology, gastroenterology, and endocrinology have adopted the principles of immune modulation, including shifting immune activation sates, from advances originally developed in oncology. Most clinical trials to date have demonstrated efficacy of cell therapies primarily in in hematologic and solid tumors, largely driven by chimeric antigen receptor T (CAR-T) cells. In contrast, mesenchymal stromal cells (MSCs) have shown limited success in oncology applications. In this article we review the most recent clinical trials involving MSCs and their promising results for patients with systemic autoimmune rheumatic diseases that have failed to respond to standard of care (SOC) therapies.

Immune reconstitution (IR) is a dynamic and sequential process that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) and cellular therapies, involving the gradual recovery of both innate and adaptive immune compartments. The success of IR is a critical determinant of clinical outcomes, including the risk of graft-versus-host disease and graft-versus-leukemia effects. In the context of allo-HCT, IR shaped by various factors, including transplantation modalities, conditioning regimens, therapeutic interventions, and post-transplant strategies. The kinetics and quality of IR following chimeric antigen receptor T-cell (CAR-T) therapy are also shaped by several factors, such as lymphodepleting chemotherapy, CAR construct design, and the patient's baseline immune status. In particular, B-cell-targeted CAR-T therapy frequently results in B-cell aplasia, hypogammaglobulinemia, and immune exhaustion, necessitating improved monitoring and post-treatment interventions. These immunologic effects highlight the need for improved post-treatment monitoring and supportive interventions to reduce infection risk and ensure sustained immune recovery. To better characterize IR across both allo-HCT and CAR-T settings, advanced immune profiling technologies, such as flow cytometry and single-cell RNA sequencing, are providing new insights into the dynamics of immune recovery. Here, we summarize current knowledge on IR kinetics and evaluate the impact of different transplant and CAR-T settings. We then discuss personalized strategies to optimize immune monitoring and therapeutic approaches for recipients of allo-HCT and CAR-T therapies.

Chimeric antigen receptor T cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has emerged as a novel and effective modality for the treatment of relapsed or refractory multiple myeloma (RRMM), achieving remarkable therapeutic outcomes. However, relapse remains a major problem impeding the long-term efficacy of this therapy, with antigen-negative relapse being a particularly challenging issue. The mechanisms underlying BCMA antigen-negative relapse encompass a spectrum of phenomena, including diminished or lost tumor antigen expression, BCMA shedding, impaired antigen presentation, trogocytosis, antigen mutations, and alternative splicing. To overcome the problem of antigen-negative relapse in BCMA CAR-T therapy, a variety of strategies are being explored. These include dual/multi-specific CAR-T cell therapy, combination therapies with antibody-drug conjugates (ADCs) or bispecific T-cell engagers (BiTEs), integration with hematopoietic stem cell transplantation (HSCT), identification of novel targets, and the development of innovative cell therapies such as CAR-NK and CAR-M (CAR-Macrophage). Additionally, the optimization of CAR-T cells through gene editing technologies to enhance their durability and anti-tumor activity is a burgeoning area of research. In future, targeted BCMA CAR-T therapy is poised to place greater emphasis on individualization and precision medicine, combining multiple therapeutic approaches to reduce the incidence of relapse, thereby improving treatment efficacy and longevity.

Transplantation tolerance is an immunologic state in which a transplant recipient's immune system does not mount a destructive immune response to an allograft. Tolerance offers an alternative to lifelong immunosuppression, potentially extending both allograft and patient survival by reducing transplant-related morbidity. Currently, the only clinically relevant approaches to achieve allograft tolerance rely on induction of donor hematopoietic chimerism through bone marrow or hematopoietic cell transplantation. There are two known types of T cell tolerance to alloantigens - central and peripheral. In central tolerance, alloantigen presentation in the thymic medulla results in clonal deletion of alloreactive immature lymphocytes. Peripheral tolerance is mediated by development of tolerogenic cell populations such as immature dendritic cells and regulatory T cells which suppress or delete alloreactive immune cells in the periphery. As the signaling molecules secreted by immune cells to orchestrate immune responses, cytokines are important in development of both central and peripheral tolerance and are critical in mediating both allograft rejection and tolerance. Understanding the immunology underlying the effects of cytokines on the immune system can help us to better understand their role in tolerance and to leverage that understanding to more reliably and safely induce transplantation tolerance.

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.

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.

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 (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.