Novel immunotherapies in lymphoid malignancies

Abstract

The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens.

Pembrolizumab (Keytruda)

“…As aforementioned, in Hodgkin lymphoma chromosome 9p24 amplification may account for the over-expression of PDL1 and PDL2. 12,58 …”

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…5,74 119 An additional candidate for combination therapy with checkpoint blockade is the family of chromatin-modifying agents, including hypomethylating agents and histone deacetylase (HDAC) inhibitors. These agents mediate direct apoptosis of CHL cell lines in in vitro studies but have additional effects that may cooperate with checkpoint blockade to increase antitumor immunity.…”

Antibody darts on target for acute myelogenous leukemia

“…AML, acute myelogenous leukemia; VL, light chain; VH, heavy chain; CD3z, zeta chain of CD3; Co-stim, costimulatory molecules. trials the CD19xCD3 BiTE blinatumomab has shown efficacy in early trials of relapsed lymphomas (1,2). In a separate development the MacroGenics company developed a DART bispecific antibody (20).…”

“…In the field of hematologic malignancies powerful antibody therapies have successfully been used to target B-lymphocyte malignancies. Antibodies have been used alone, but can be engineered linking them to toxins or to T lymphocytes, either joined to the zeta chain of the T cell receptor (chimeric antigen receptors), or through bi-specific antibodies binding T cells by anti CD3 to the lymphoid target through, for example the anti CD19 variable portion [reviewed in (1)]. Clinical trials clearly confirm the power of strategies which bring T cells with their cytotoxic potency into close proximity with surface antigen targets on the malignant cell (2)(3)(4).…”