Pediatric Cancer Immunotherapy: Opportunities and Challenges

Abstract

Cancer immunotherapies, widely heralded as transformational for many adult cancer patients, are becoming viable options for selected subsets of pediatric cancer patients. Many therapies are currently being investigated, from immunomodulatory agents to adoptive cell therapy, bispecific T-cell engagers, oncolytic virotherapy, and checkpoint inhibition. One of the most exciting immunotherapies recently FDA approved is the use of CD19 chimeric antigen receptor T cells for pre-B-cell acute lymphoblastic leukemia. With this approval and others, immunotherapy for pediatric cancers is gaining traction. One of the caveats to many of these immunotherapies is the challenge of predictive biomarkers; determining which patients will respond to a given therapy is not yet possible. Much research is being focused on which biomarkers will be predictive and prognostic for these patients. Despite many benefits of immunotherapy, including less long-term side effects, some treatments are fraught with immediate side effects that range from mild to severe, although most are manageable. With few downsides and the potential for disease cures, immunotherapy in the pediatric population has the potential to move to the front-line of therapeutic options.

Biomarker recommendation for PD‐1/PD‐L1 immunotherapy development in pediatric cancer based on digital image analysis of PD‐L1 and immune cells

“…These arguments speak against further development of anti‐PD‐1/PD‐L1 monotherapy in these indications. However, circumstances could be different if pre‐treatment could enhance the induction of PD‐L1 and TIL markers in tumors to allow subsequent anti‐PD‐1/PD‐L1 therapeutic intervention . Also, it is important to remember that the antitumor effect of immunotherapies is not only dependent on the quantity of the immune cells present in the tumor, but also on the quality and function of these cells, aspects not evaluated in this morphological study .…”

“…Despite the success, limited treatment approaches are available in solid neoplasia such as sarcomas and primary central nervous system cancer , which is associated in part with acquired chemotherapy resistance . Thus, novel treatment options like anti‐PD‐1/PD‐L1 checkpoint inhibitors could offer a therapeutic alternative to fulfill the current needs . Such biologicals have been approved for the treatment of a variety of adult tumor types, unleashing antitumoral T‐cell adaptive immune responses suppressed by a PD‐1/PD‐L1 receptor‐ligand interaction between effector immune cells and tumor parenchyma .…”

“…A critical aspect to successfully develop anti‐PD‐1/PD‐L1 immunotherapies is the identification of individuals with a high probability of responding to treatment . In adults, this stratification is currently performed by selecting patients with elevated levels of PD‐L1 immunostaining in tumor areas by means of proprietary and/or developed companion diagnostic tests .…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…Some of the pediatric immune-based approaches have received FDA approval, including monoclonal antibodies (mAbs), checkpoint inhibitors, bispecific T-cell engagers (BiTEs), and chimeric antigen receptor-modified T (CAR-T) cells. However, some immunotherapy protocols are still under way to be examined, such as vaccines and oncolytic virotherapies (169). CAR-T cells are genetically engineered to target surface antigens on tumor cells and have exhibited good efficacy for treatment of the hematological malignancies (170).…”

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

“…Emerging reports show checkpoint inhibitors elicit poor responses in pediatric patients 61 . This has been ascribed to a lack of neoantigens 62 .…”