Highlights from Recent Cancer Literature

Abstract

Despite the clinical success of CAR T cells for treating hematological malignancies, the potential of CAR T cells for treating pediatric central nervous system (CNS) tumors remains unclear. In Group 3 medulloblastoma models, Vitanza and colleagues observed that cytotoxicity in vivo using HER2-specific CAR T cells required medium and long-length extracellular spacers. Using the product optimized preclinically, they initiated a clinical trial for recurrent HER2+ CNS tumors (BrainChild-01). In their first three subjects (one high-grade glioma and two metastatic ependymomas, ages 15 to 26), repeated doses of a CD4+CD8+ HER2 CAR T cell were directly infused into either the tumor cavity or the ventricular system. While HER2+ CAR T cells were not detected in cerebrospinal fluid or serum after infusion, non-CAR T-cell populations as well as several inflammatory cytokines, including the chemokine ligand CXCL10, were strikingly elevated, consistent with local CNS inflammation. Neuroimaging also showed features suggestive of an inflammatory response.Expert Commentary: This pilot study of locoregional delivery of CAR T cells shows the feasibility of delivering CAR T cells to pediatric brain tumors. This opens the door to studying other relevant epitopes and combinations.Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, Künkele A, et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nature Medicine, Published July 12, 2021; DOI: 10.1038/s41591-021-01404-8.Although the mechanisms of acquired resistance to the FLT3 inhibitor gilteritinib have been well defined, little is known about the adaptative responses that lead to persistence and eventual resistance. Joshi and colleagues utilized genomic, proteomic, and metabolomic approaches as well as genetic and pharmacologic screening to define the stepwise progression toward gilteritinib resistance in acute myeloid leukemia. Resistance occurred through a biphasic pattern with an early stromal ligand-dependent persistence stage, followed by a later ligand-independent NRAS mutant–dependent resistance stage. Persistence was mediated by multiple convergent pathways that resulted in metabolic reprogramming, MAPK/PI3K pathway reactivation, and AURKB dependency.Expert Commentary: This study suggests that upfront treatment with the combination of an AURKB inhibitor with gilteritinib can target persister cells and prevent acquired resistance.Joshi SK, Nechiporuk T, Bottomly D, Piehowski PD, Reisz JA, Pittsenbarger J, et al. The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance. Cancer Cell 2021;39:999-1014.e8. DOI: 10.1016/j.ccell.2021.06.003.In a recent analysis of high-grade serous ovarian carcinomas, Pietila and colleagues showed that chemotherapy-induced changes in the extracellular matrix components of the tumor microenvironment (also known as the matrisome) contributed to the outgrowth of chemo-resistant cells. Defining the matrisome in pre- and post-chemotherapy metastatic and primary tumor samples, the authors identified alterations in a number of core extracellular matrix proteins, including collagen VI, which could dictate response to platinum treatment and were associated with patient survival.Expert Commentary: This study supports a model in which extracellular matrix remodeling, driven by both the metastatic microenvironment and chemotherapy, promotes chemoresistance by providing a permissive niche for the outgrowth of resistant cells.Pietila EA, Gonzalez-Molina J, Moyano-Galceran L, Jamalzadeh S, Zhang K, Lehtinen L, et al. Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nature Commun 2021;12:3904. DOI: 10.1038/s41467-021-24009-8.Most immunocompetent mouse models for glioblastoma have high mutational burdens and respond to checkpoint blockade immunotherapy (CBI). In contrast, human glioblastomas have low mutational burdens and are resistant to CBI. Simonds and colleagues demonstrated that CBI responsiveness in human and murine tumors was associated directly with the abundance of T cells and dendritic cells and inversely associated with the abundance of PD-L1+ tumor-associated macrophages. SB28, an immunocompetent mouse model of glioblastoma with low mutational burden, demonstrated CBI responsiveness in tumors grown subcutaneously but not intracerebrally. CBI responsiveness in subcutaneous tumors required CD4+ T cells and natural killer cells, but not CD8+ T cells. Recombinant FLT3 ligand expanded dendritic cells, improved antigen-specific T-cell priming, and prolonged survival of mice with intracerebral SB28 glioblastoma, but at the cost of increased Tregs.Expert Commentary: These observations suggest that poor antigen presentation in the brain contributes to CBI resistance. Dendritic cells and PD-L1+ tumor–associated macrophages represent targetable cell types.Simonds EF, Lu ED, Badillo O, Karimi S, Liu EV, Tamaki W, et al. Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma. J Immunother Cancer 2021;9:e002181. DOI: 10.1136/jitc-2020-002181.The five-year survival of patients with high-risk neuroblastoma is below 40% despite demanding treatments including surgery, chemotherapy, radiation, and immunotherapy. There is therefore an unmet need for improved strategies for treating neuroblastoma. Nile and colleagues analyzed radiosensitivity of a panel of neuroblastoma and glioblastoma cell lines upon metabolic perturbation using inhibitors of glycolysis (the synthetic glucose analog 2-deoxyglucose) or the respiratory chain (the diabetes drug metformin). The combination of 2-deoxyglucose with metformin resulted in enhanced radiosensitivity, and the triple combination caused G2–M arrest, followed by apoptosis. Metabolomic and bioenergetic profiling revealed a robust depletion of key metabolites from glycolysis as well as from mitochondrial respiration and reduced generation of ATP.Expert Commentary: This study suggests that dual metabolic targeting using 2-deoxyglucose with metformin enhances the radiosensitivity of neuroblastoma tumors and overcomes radioresistance, which could lead to prolonged survival.Nile DL, Rae C, Walker DJ, Wadington JC, Vincent I, Burgess K, et al. Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells. Cancer Metabolism; Published online May 19, 2021; DOI: 10.1186/s40170-021-00258-5.Checkpoint blockade immunotherapy (CBI) impedes the engagement of inhibitory receptors in cis on T cells, improving T-cell responses. Anti-CTLA4 CBI also depletes regulatory T cells (Treg), relieving immunosuppression to enhance the antitumor response. Marangoni and colleagues showed that anti-CTLA4 antibodies may enhance local activation and proliferation of Tregs within tumors. Intravital microscopy visualization of Treg interactions with dendritic cells (DC) within tumors revealed that Tregs exhibited unstable interactions with DCs in tumors that were sufficient for sustaining Treg proliferation and suppressive function. Mechanistically, Tregs removed costimulatory ligands on DCs (CD80/CD86), promoting immunosuppression. Anti-CTLA4 increased levels of CD80/CD86 on the surface of DCs, potentially improving costimulation of antitumor T cells. Increased CD80/CD86 on DCs also led to increased activation, proliferation, and accumulation of Tregs in tumors. Furthermore, with anti-CTLA4 CBI, Tregs still retained alternative means of immunosuppression, making their expansion with anti-CTLA4 CBI an undesirable consequence.Expert Commentary: Anti-CTLA4 CBI impedes Treg-mediated removal of costimulatory ligands on DCs, but it also increases the activation and expansion of Tregs in tumors, which could promote immunosuppression in cancers.Marangoni F, Zhakyp, A, Corsini M, Geels SN, Carrizosa E, Thelen M, et al. Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop. Cell; Published online June 17, 2021; DOI: 10.1016/j.cell.2021.05.027.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.