1Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Korea.
2Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
3Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea.
4Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Recently, successful cancer immunotherapy has aroused great interest in application of this approach in hematological malignancies. Immune responsiveness is a key clinical feature of hematological malignancies. Indeed, the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) largely derives from graft-versus-tumor effects that highlight the ability of the immune system to specifically and effectively eliminate tumors . Here, we describe the status of cellular immunotherapy in hematological malignancies and discuss its future perspectives.
DCs are professional antigen-presenting cells that serve as an essential link between innate and adaptive immune systems. For successful clinical application, factors such as choice of antigen source, DC vaccine formulation, delivery system, adjuvants, immunomodulation, and treatment schedule should be considered.
The key component of adoptive T cell therapy is generation of functional tumor-specific T cells without immune tolerance to self-antigens. This can be accomplished by genetic modification of patient T cells using genes encoding CARs. Recently, the third-generation of CAR T cells has been developed, which includes an additional co-stimulatory domain, such as CD28 plus 4-1BB or CD28 plus OX40 together with CD3zeta along with the specific target. Results from several clinical trials in different settings including CAR design, culture techniques, lymphodepleting strategies, and target diseases, have provided valuable insights, and CAR T cells are emerging as a powerful therapy in hematologic malignancies . Most clinical successes of CAR T cell therapy are recorded in the setting of B-cell malignancies, by targeting CD19 (Table 1). Several B cell antigens, such as CD20, CD22, CD23, and CD38 are under evaluation as alternative CAR T cell targets in B-cell malignancies. However, targets that are expressed on majority of tumor cells but absent from normal cells and are thus more selective, should be developed to avoid on-target toxicity to normal cells following adoptive transfer of CAR T cells in patients. In MM, several CARs targeting BCMA, CD38, CD138, or CS-1 have shown preclinical efficacy. Currently, two clinical trials in Hodgkin's lymphoma are evaluating efficacy of CD30-directed CAR T cell therapy. Preclinical studies using anti-CD123 CAR and anti-CD44v6 CAR are under evaluation in AML with promising results. However, neither of these antigens is truly tumor-specific and significant hematopoietic or epithelial toxicity may be expected. "Bio-degradable" CAR T cells and other options regarding suicide mechanisms can be used to extinguish unwanted CAR T cell activity. Careful analysis of early-phase clinical trials using anti-CD19 targeting in B-cell malignancies has uncovered information regarding toxicity and continues to inform the next generation of CAR T cell trials. These observations will prove useful in extending this modality to other hematologic malignancies and solid tumors in the near future .
NK cells are killer cells that have immune regulatory action against infected or malignant cells without prior sensitization. It is well known that NK cells can be long-lived, remember past exposures, and interact with MHC class I molecules to acquire full function. NK cell function is tightly regulated by signals from natural cytotoxicity receptors, CD16 receptor for antibody-dependent cellular cytotoxicity (ADCC), C-type lectins, and killer cell immunoglobulin-like receptors (KIR) . The first NK cell immunotherapy in humans was performed with administration of IL-2 or adoptive transfer of IL-2-stimulated
Cancer immunotherapy using DCs, CAR T cells, and NK cells may be used in combination with other therapies including chemotherapy, radiation therapy, molecular gene targeting, adjuvants, or immune modulators such as checkpoint blockades and IMiDs, for changing the immunosuppressive nature of a tumor towards an immunitysupporting microenvironment. This will have high impact on enhancing therapeutic immunity in hematological malignancies by simultaneously enhancing potency of immune responses and offsetting immunosuppressive pathways.