Immune-based therapies for childhood cancer

Abstract

After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in B-ALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms.

CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia

“…Combination or tandem CARs, which join 2 antigen-recognition moieties, may prevent relapses due to escape variants but need further studies. In this regard, the group at the National Institutes of Health has developed CAR T cells targeting the B-cell antigen CD22, 40,75,76 which can be used for treating CD19-negative relapse and could be combined with a CD19-directed CAR in the future.…”

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…Recently, eliciting antitumor immunity has been proposed to be a promising option for treating high-risk childhood neuroblastoma (13,14). However, tumor-induced inflammation limits efficient antitumor immune responses through recruitment of various suppressive immune cell types (15), including myeloidderived suppressor cells (MDSC) and "M2-biased" tumor-associated macrophages (TAM) (16)(17)(18)).…”

Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD

“…CARs typically contain an extracellular antibody-derived single-chain Fv linked to a T-cell receptor (TCR) signaling component (z chain of CD3), and 1 to 2 costimulatory molecules (ie, CD28, 41BB, and OX40). [11][12][13][14] This provides major histocompatibility complex (MHC)-independent T-cell activation and co-stimulation. Initial reports of CAR T cells targeting CD19 for ALL showed remarkable results with remission rates of over 70% in relapsed refractory patients.…”