Clinical Developments in Hematologic Malignancies and Future Obstacles

Overview

Over the past few years, clinical blood cancer research has expanded significantly, and arguably no field has attracted as much attention as immunotherapy, particularly treatment with immune-checkpoint inhibitors like the PD-1 antibody nivolumab for classic Hodgkin lymphoma. Even though all of these cutting-edge medications show potential, CAR T cell-based therapies have been the focus of the most excitement among immunotherapies for hematologic malignancies. Rapid and profound responses have been attained employing CAR T cells targeting B-cell maturation antigen in multiple myeloma, demonstrating the therapeutic potential of these approaches. As it relates to extending response and averting relapse, ongoing research is being done to improve safety as well as efficacy. According to Anderson, efforts to increase efficacy include modifying CAR T-cell products to choose for central memory cells and controlling the host to attempt to prolong the lifespan of the immune response in order to sustain therapeutic benefit.

Since it is difficult to find the right cell-surface targets for myeloid malignancies, CAR T cell-based therapies for hematopoietic cancers are not yet as effective as they could be for some B-cell malignancies. Another example of how blood cancer research is frequently at the forefront of cancer research is the adaptation of CAR T cell-based therapeutics for the treatment of solid tumors. This field is another one that is receiving a lot of attention. The use of CAR NK cells, which is now being investigated, is a logical next step, according to Dalla-Favera, who believes that CAR therapy is still in its infancy because only a few targets and T cells have been employed. The cost and time involved in producing CAR T cell-based therapies, which need to be made specifically for each patient, is another barrier to their widespread use. Bispecific antibodies, which are less expensive, over-the-counter immunotherapies that have attracted a lot of interest, are being further developed in part due to this characteristic. According to Dalla-Favera, "we will witness the adoption of bispecific antibodies, which may replace or complement CAR T." He continues, "The trials are in the early phases." A combination of immunological strategies may ultimately be required to achieve persistent responses.

Although the excitement surrounding CARs and immune-checkpoint blockage, immunotherapies are by no means the only area in which clinical success in hematologic malignancies is being made: The hematologic-oncology research community has responded well to targeted medicines as well. We have completed 30 years of research on the genetics of blood cancer, and the time has come to use that knowledge for therapy, according to Dalla-Favera. Now that targeted medications have been approved for use, blood cancer is cancer and we are seeing those most frequently.

Although targeted medicines can have substantial effects when administered to the right patients, the emergence of resistance is a significant barrier. One strategy for combating resistance is to use next-generation medications that attack the target of interest from a new angle, for as by utilizing an allosteric rather than a direct inhibitor. Focusing on treating patients when the number of cancer cells is low through early cancer detection or relapse prevention reduces the likelihood that resistant cells already exist within the cancer-cell population. This is another strategy for dealing with resistance. The treatment of side effects, which can result from on-target effects or direct effects of a particular medicine, is another challenge faced by targeted therapies.

Another area of active study is finding ways to affect "undruggable" targets such as transcription factors, which are changed in a significant number of malignancies. Furthermore, traditional radiation and chemotherapy still have a place in treatment at least for the time being. According to Anderson, "I think that we will employ traditional medicines, but we will ideally use them in a more educated way based upon preclinical study." For instance, alkylating chemicals damage DNA, while proteasome inhibitors prevent, among other things, DNA damage repair. Alkylating drugs and proteasome inhibitors together caused synergistic cytotoxicity in myeloma cells through the induction of DNA damage and the blocking of DNA-damage repair, according to preclinical investigations. These trials helped develop the combination of alkylating drugs, such as cyclophosphamide, and proteasome inhibitors, such as bortezomib, which is now frequently used as the first line of treatment for multiple myeloma.

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