Immunologic Treatments of Hematologic Malignancies: Moving Beyond Salvage Therapy to Curative Eradication of Minimal Residual Disease
Recent advances in the field of immunology, including immune evasion, genetic engineering, and adoptive immunotherapy, have generated novel immune-based strategies and improved the utility of existing options, such as allogeneic hematopoietic stem cell transplantation (HSCT). These new approaches offer vast clinical promise to impact a wide array of diseases, including acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), Hodgkin and non-Hodgkin lymphoma, and myeloma, as well as non-malignant hematologic disorders such as sickle cell anemia and other inherited hematologic or metabolic diseases.
Among the most exciting emerging therapies are T-cell checkpoint inhibitors, which non-specifically amplify immune responses and therefore have significant off-target events. Antibody-based therapies interfere with inhibitory receptors, such as the PD-1 receptor on T cells and its ligand PDL-1/2 on either cancer cells or in the microenvironment. Because these monoclonal antibodies unleash exhausted T cells to respond to tumors with potent efficacy and strong clinical profiles, they may provide valuable new therapeutic options to transform patient care in hematologic cancers.
Another highly promising emerging area is engineered adoptive T-cell cell therapy, with compounds demonstrating therapeutic activity against a broad variety of lymphoid malignancies. To produce these therapies, the patient’s or donor’s T cells are engineered ex vivo to express a recombinant chimeric antigen receptor (CAR) with an extracellular antibody-derived domain for binding with a tumor-specific antigen (TSA) and an intracellular component of a T-cell receptor (TCR)-derived signaling moiety for T-cell activation. This CAR T-cell approach harnesses the potent T cell cytolytic mechanisms directed by the specificity of the antibody domain, allowing for the use of T cells in a specific, but major histocompatibility complex (MHC)-unrestricted, manner. Recent studies have demonstrated significant and durable efficacy using these studies to produce curative results in specific patient populations, which researchers aim to replicate in additional settings.
These important developments have driven new perspectives on how to manipulate the immune system with the goal of curing hematologic diseases that have historically been deemed fatal. Today there are exciting research opportunities to expand the utility of these novel approaches in the near term and support their implementation far beyond hematologic diseases in the future.
Advancing Treatments with Curative Potential: Priorities to Optimize Immunotherapies
Next-generation clinical studies will address important questions about emerging immunologic therapies but require an improved understanding of the basic biology of the immune system, including adaptive immunity, innate immunity, adjuvants, and tumor immune-surveillance.
As the body of evidence continues to grow on the potential applications for advanced immunotherapies, next-generation research must address the ability of these checkpoint or adoptive CAR T-cell strategies not only to successfully treat, but to potentially cure hematologic cancers. This will require specific research programs to fully understand the optimal role for these therapies within the continuum of care.
|1.1||Assessments to improve patient stratification will optimize the use of these therapies for both lymphoid and myeloid malignancies, and in acute or chronic malignancies.|
|1.2||Research must determine in which diseases and under which circumstances these checkpoint blockers and CAR T-cell therapies may be employed as frontline approaches, or if they would be of greater efficacy in the context of treating minimal residual disease.|
|1.3||The optimal approach for these therapies is not yet clear; advanced studies will elucidate the potential benefit in combining these promising approaches and whether patients can be better identified a priori for these therapies.|
Much remains to be understood about immunotherapies in order to facilitate their broad use in the treatment of hematologic disorders. While studies to date have demonstrated significant potential applications, longer-term studies are necessary to further improve the profile of these therapies, including enhancing their overall efficacy while reducing associated toxicities. Critical near-term priorities will help achieve these objectives.
|2.1||Evaluation of the mechanisms of cytokine release syndrome (CRS), which has been observed in several patients receiving this therapy, will require a careful grading scheme to predict toxicity and guide the development of preventive and therapeutic strategies. An important issue for consideration is whether CRS is required to achieve a durable or potent response to CAR T-cell therapy.|
|2.2||The optimal selection of cells and vector design for CAR T-cells must be assessed. While current strategies utilize bulk T cells, the use of specific T-cell subsets (CD4+ vs. CD8+ or central memory vs. effector memory T cells) or natural killer (NK) cell subsets must be better understood. Additional issues include the choice of optimal vector designs and the best co-stimulatory cassettes required for potency.|
|2.3||Studies are essential to specifically address CAR T-cell survival and function. Studies are required to understand the factors that permit or inhibit long-term survival and the development of exhaustion. Further research is needed to determine whether the phenotypic markers and pathways for development of memory/exhaustion in these modified T cells and NK cells will be similar or distinct from unmodified T cells.|
|2.4||Target identification is another important issue to advance the field. While targeting CD19 appears to be promising, it results in loss of B-cell immunity and requires prolonged immunoglobulin replacement therapies and/or allo-transplantation. Minimizing the off-tumor target-mediated toxicity of both CAR T-cell and checkpoint blockade therapies would help optimize their utility. Identification of immunogenic leukemia-specific antigens that can readily be targeted would help preclude this problem.|
|2.5||Finally, it will be necessary to create additional infrastructure within health-care systems, increasing capacity for production to support availability for more patients and reduce costs.|
After years of continued advancements, allogeneic HSCT has become the most validated immunotherapy available today, used to treat and often cure many hematologic diseases. For example, in the case of myeloma, the combination of HSCT and advanced targeted therapies has dramatically improved long-term survival rates. Yet despite its value, serious side-effects associated with this treatment persist, leaving important research questions that must be answered to improve its safety and effectiveness.
|3.1||New studies are required to help overcome current limitations of both cord blood and haplo-identical transplants, optimizing both donor selection and expansion of cord blood stem cells in order to advance the safety and success of this treatment.|
|3.2||Advances that improve the safety of transplants by reducing relapse (improving graft-versus-leukemia (GVL) responses) and rates of complications (e.g., the incidence of graft-versus-host-disease (GVHD)) will allow for further expansion of this modality. Future research will illustrate whether the GVL effects of allogeneic HSCTs can be harnessed without further aggravating its toxicities, and new approaches to mitigate GVHD will improve patient outcomes after an allogeneic HSCT.|
|3.3||4.3.3. Studies that can identify immunogenic minor antigens and novel molecular targets in various immune cells (e.g., T cells, Tregs, B cells, NK cell subsets, antigen-presenting cell (APC) subsets), map their interactions, and continue to analyze the immune repertoire will offer insights on how to mitigate GVHD while harnessing GVL responses.|
|3.4||Identification of patients who will respond to these therapies is needed, in addition to randomized clinical trials to evaluate the relative benefit of emerging immunotherapies against allogeneic HSCTs. Further, the cost, regulatory, and accessibility of these immune-based strategies must be improved to facilitate broad utilization by all patients who need them.|