Special Session 2 - Immunotherapy for Cancers in Children

The demonstrated capacity of immune cells to kill tumor cells suggests that they could be used to treat cancer. Conceivably, immune cells could overcome the resistance of cancer cells to standard treatment modalities while sparing normal tissues. Results of recent clinical trials with autologous T cells redirected against leukemia or lymphoma cells through the expression of anti-CD19 chimeric antigen receptors (“CAR”) have fully validated the potential of immune cells as living drugs. Dramatic tumor responses were observed in patients who had become resistant to all other available treatment. The clinical efficacy of these early immune cell-based therapies has stimulated great interest in this area of translational research, encouraged efforts to further improve CAR-T cell function, and renewed the enthusiasm for exploring the potential of other immune cells.. 

Simplifying ex vivo cell processing, widening the range of targetable antigens, and generating safer and more effective cell products are important objectives for the future. To overcome the need of developing an individual CAR for each target and allow the targeting of multiple cancer antigens simultaneously, we developed a CD16-based receptor which endows T cells with antibody-dependent cell cytotoxic capacity. This receptor has shown promise in preclinical studies and is currently being tested in clinical trials. We have also generated ways to target T-cell malignancies with CAR-T cells. Finally, methods to expand and genetically engineer NK cells have been established and validated in a clinical-grade setting, leading to several ongoing clinical trials. These immune cell therapy approaches are being explored with the vision of building an array of immunotherapeutic options that can complement, and ultimately replace, standard therapy of cancer.

Natural killer (NK) cells are normal white blood cells capable of killing cancer cells without prior sensitization. Unlike allogeneic T cells, NK cells do not cause graft-vs-host disease. Furthermore, allogeneic NK cell infusions are attractive for cancer therapy because of non–cross-resistant mechanisms of action and minimal overlapping toxicities with standard cancer treatments. Although NK therapy is promising, many obstacles will need to be overcome, including insufficient cell numbers, effector dysfunction, exhaustion, and tumor cell evasion. In this lecture, we will review recent NK cell biology studies and the advancements in biotechnology. We will examine novel approaches of NK cell therapy that may improve therapeutic efficiency and reduce side effects, including immunogenetic-based donor selection, refined NK cell bioprocessing, and novel augmentation techniques, to improve NK cell function and to reduce tumor resistance. Although data from clinical trials are currently limited primarily to hematologic malignancies, broader applications to a wide spectrum of solid cancers are under way. The unique properties of human NK cells may open up a new arena of novel cell-based immunotherapy against cancers that are resistant to contemporary therapies.

Over the past decade, there are many new advances in the management of cancers that included targeted therapies by either small molecules inhibitors or immunotherapy. Immunotherapy can further be classified into different categories such as active immunotherapy, passive immunotherapy, adoptive immunotherapy and immune check point inhibitor treatment. The active immunotherapy includes cytokines therapy and tumor vaccine. For children cancers, interferon alpha as a maintenance therapy for chronic myeloid leukemia previously and consolidation treatment for childhood nasopharyngeal cancers are examples of such approach. Tumor vaccine against GD2 for neuroblastoma is currently under clinical trial. For passive immunotherapy, use of monoclonal antibody against specific tumor associated antigen is the main strategy. This includes anti-CD20 for B-lineage acute lymphoblastic leukemia or non-Hodgkin lymphoma, anti-CD33 for acute myeloid leukemia, anti-GD2 for neuroblastoma and anti-CD30 for Hodgkin lymphomas. The newest approach is using bio-engineered bispecific antibodies that link a tumor specific antigen to cytotoxic T cells. We witnessed both success and failure of these active and passive immunotherapy approaches. They have to be used in combination with chemotherapy under most situations. For adoptive immunotherapy, it involves the use of either autologous or allogeneic immune cells. The most common forms are hematopoietic stem cells transplant (HSCT), NK cells, and CAR-T cells. In principle, the combination of both cellular and non-cellular immunotherapy can further enhance the efficacy. Finally, immune check-point inhibitors (PD-1 or PDL-1 inhibitor, CTLA-4 inhibitor) are emerging concept and PD-1 inhibitor has been used in refractory Hodgkin lymphoma with good preliminary result. Whether immune check point inhibitor can be used together with other immunotherapy remains to be explored. When using these new therapies, a totally new set of therapy-related toxicity emerged and clinicians have to be aware of these complications and know how to manage them. In summary, the new paradigm of applying immunotherapy for cancers is coming but we have to understand their respective strengths and weaknesses so they can be applied effectively. In addition, the markedly high cost of most of these therapies may limit their availability to most patients in needed. Concerted effort from both Governments and manufacturers are essential in order to improve their application to general public.