Combining CAR T Cell Therapy and Oncolytic Virotherapy for Pediatric Solid Tumors: A Promising Option

Abstract

Despite advances in treatment options, the clinical outcomes of pediatric patients with advanced solid tumors have hardly improved in decades, and alternative treatment options are urgently needed. Innovative therapies, such as chimeric antigen receptor (CAR) T cells and oncolytic viruses (OVs), are currently being evaluated in both adults and children with refractory solid tumors. Because pediatric solid tumors are remarkably diverse and biologically different from their adult counterparts, more research is required to develop effective treatment regimens for these patients. Here, we first summarize recent efforts and advances in treatments for pediatric solid tumors. Next, we briefly introduce the principles for CAR T cell therapy and oncolytic virotherapy and clinical trials thereof in pediatric patients. Finally, we discuss the basis for the potential benefits of combining the two approaches in pediatric patients with advanced solid tumors.

Advances in cell-based delivery of oncolytic viruses as therapy for lung cancer

“…On the whole, combining CAR T cell therapy and oncolytic virotherapy in a TME should therefore benefit from an immediate function of CAR T cells followed by OV-stimulated immune activation that causes a more effective lysis of heterogeneous cancer cell populations, which could mitigate tumor relapse encountered by CAR T cell therapy due to antigen escape. 211 , 212 , 213 However, one has to reckon with the most common toxicities of CAR T cell therapy, which consist of release syndrome (CRS) often concurrent with or shortly followed by immune cell-associated neurotoxicity syndrome (ICANS). Also whether a combination with OV therapy mitigates CRS and ICANS is not clear, also due to the fact that so far this combinational therapy is only being investigated in one clinical trial, in which HER2-CAR virus-specific T cells and a binary oncolytic adenovirus are being used to treat patients with advanced HER2-positive solid tumors ( NCT03740256 , Table 3 ).…”

Gene therapy in cancer

“…45 There are two important acute toxicities of CAR-T cell treatment which are the cytokine release syndrome and CAR-T cell-related encephalopathy syndrome. 46 The efficacy and safety of CAR-T cell therapy can be changed by engineering strategies. CARs have modular components, and therefore the optimal molecular design of the CAR can be achieved through many variations of the constituent protein domains for more widespread use in anticancer therapy and to expand the clinical benefits of CAR-T cells in patients with diverse cancers.…”

“…Therefore, more studies are required in the future. [45][46][47][48] In 2017, the US Food and Drug Administration (FDA) approved chimeric antigen receptors that use Tisagenelecleucel (Kymriah) and Aksicabtageneeciloleucel (Yescarta), synthetic designed receptors, as a new cellular immunotherapy. 49,50 Commercial CAR-T cell therapies approved by the EMA and FDA are given in Table 1.…”

“…Toxicities related to CAR‐T cell therapy can be classified as on‐target on‐tumor toxicity, on‐target off‐tumor toxicity, off‐target toxicity, neurotoxicity, genotoxicity and immunogenicity 45 . There are two important acute toxicities of CAR‐T cell treatment which are the cytokine release syndrome and CAR‐T cell‐related encephalopathy syndrome 46 . The efficacy and safety of CAR‐T cell therapy can be changed by engineering strategies.…”

“…In other respects, increasing the complexity of CAR designs and the gene editing of T cells might amplify the risks associated with CAR‐T cell therapy and the modification of CAR‐T cells could increase effect of these adverse events. Therefore, more studies are required in the future 45–48 …”