JITC Editor Picks
Juliane Schuhmacher, Sonja Heidu, Torben Balchen, Jennifer Rebecca Richardson, Camilla Schmeltz, Jesper Sonne, Jonas Schweiker, Hans-Georg Rammensee, Per Thor Straten, Martin Andreas Røder, Klaus Brasso, Cécile Gouttefangeas
Journal for ImmunoTherapy of Cancer 2020;8:e001157 (12 November 2020)
Research
Summary:
Effective therapeutic vaccines for cancer immunotherapy must elicit both cytotoxic and helper T cell responses in order to coordinately provide durable anti-tumor efficacy. Taking advantage of the fact that synthetic long peptides (SLPs, 15-35 amino acid residues long) activate both CD4+ T cells and CD8+ T cells by cross-presentation, Juliane Schuhmacher et al developed a 20-residue vaccine for prostate cancer derived from Ras homolog gene family member C (RhoC), which shows limited expression in normal cells but is abundant on advanced cancer cells and metastases. In a first-in-human phase I/II study, 22 patients who had previously undergone radical prostatectomy received six every-other-weekly subcutaneous injections of 0.1 mg of a single RhoC-derived SLP emulsified in Montanide ISA-51, followed by five additional doses spaced four weeks between injections. Of the 21 evaluable patients, 18 (86%) developed T cell responses against the vaccine during dosing and 19 (90%) had measurable response during the 13 month follow-up period. Among the patients with the strongest T cell responses, regulatory T cell counts decreased by almost two-fold. CD4+ T cell responses were observed in 17 of 18 (94%) patients. At least three different HLA-class II peptides derived from the vaccine were shown to be presented on various HLA-class II alleles and one HLA-class I peptide was found to presented by the HLA-B*27:05 allele. Although clinical benefit was not an endpoint, three patients progressed biochemically during follow-up, although one patient did show a decreased PSA doubling time on study. No patients developed clinical recurrence. No toxicities led to discontinuation treatment in any patient, and the most frequent treatment-related events were grades 1 or 2 fatigue and injection site reactions.
Iuliia Efimova, Elena Catanzaro, Louis Van der Meeren, Victoria D Turubanova, Hamida Hammad, Tatiana A Mishchenko, Maria V Vedunova, Carmela Fimognari, Claus Bachert, Frauke Coppieters, Steve Lefever, Andre G Skirtach, Olga Krysko, Dmitri V Krysko
Journal for ImmunoTherapy of Cancer 2020;8:e001369 (13 November 2020)
Research
Summary:
Immunogenic cell death, initially conceptualized in cancer cells undergoing apoptosis, is characterized by the release of damage-associated molecular patterns (DAMPs) such as ATP, high-mobility group box 1 (HMGB1), calreticulin (CRT) and type I interferons (IFNs). Hypothesizing that alternate cell death pathways may also adjuvant anti-tumor immunity, Iuliia Efimova and colleagues characterized DAMP production and immunogenicity both in vitro and in vivo for cancer cells undergoing the iron-dependent cell suicide mechanism ferroptosis. The GPX4 inhibitor RSL3 was shown to induce ferroptosis in fibrosarcoma cell lines, even in the presence of known inhibitors of other cell death pathways. Surprisingly, ferroptotic cells exposed to RSL3 for 24 hours did not induce maturation in bone-marrow derived dendritic cells (BMDCs), despite being efficiently phagocytosed. Cells exposed to PSL3 for only 1 hour, however (early in ferroptosis, with only 6% of cancer cells double positive for Annexin-V/Sytox), induced CD80, CD86 and MHCII expression in CD11c+ BMDCs as well as IL-6 production. The time course of DAMP secretion was shown to vary, with ferroptotic cancer cells starting to release between hours 3 and 6 of RSL3 treatment, but ATP being depleted by 24 hours. In murine models, vaccination with early ferroptotic fibrosarcoma cells prevented tumor establishment upon rechallege with viable cancer cells, but no protection was seen in homozygous Rag2 knockout mice, indicating that mature B and T cells are necessary for anti-tumor effects of the vaccine. The findings expand upon the concept of immunogenic cell death and identify a new pathway for potential future immunotherapeutic development.
Javier Martin-Broto, Nadia Hindi, Giovanni Grignani, Javier Martinez-Trufero, Andres Redondo, Claudia Valverde, Silvia Stacchiotti, Antonio Lopez-Pousa, Lorenzo D'Ambrosio, Antonio Gutierrez, Herminia Perez-Vega, Victor Encinas-Tobajas, Enrique de Alava, Paola Collini, Maria Peña-Chilet, Joaquin Dopazo, Irene Carrasco-Garcia, Maria Lopez-Alvarez, David S Moura, Jose A Lopez-Martin
Journal for ImmunoTherapy of Cancer 2020;8:e001561 (17 November 2020)
Research
Summary:
No new drugs or combination regimens have shown overall survival benefit for synovial sarcoma for the last 40 years. Although sarcomas are generally thought to be immunologically cold tumors, Javier Martin-Broto and colleagues hypothesized that targeting tumor angiogenesis might alleviate some immunosuppression in the microenvironment and increase susceptibility to checkpoint blockade and conducted a phase Ib/II trial to test the combination of sunitinib (a multi-tyrosine kinase inhibitor that inhibits angiogenesis) and nivolumab (anti-PD-1). The recommended phase II dose was identified after observing three dose-limiting toxicities in six accrued patients, consisting of grade 3 fatigue (n=2) and grade 4 septic shock (n=1). Among the 14 evaluable patients treated with the recommended phase II dose of an induction phase of 37.5 mg sunitinib for the first 14 days and then 25 mg per day plus nivolumab 3 mg/kg intravenously every 2 weeks, there were seven partial responses per RECIST. The 6-month progression-free survival rates according to central and local assessments were 48% (95% CI 41 to 55) and 51% (95% CI 44 to 58), respectively. Median overall survival was 24 months. In an accompanying translational study of expression changes in a panel of 732 genes related to tumor immune response, 50 genes were shown to have prognostic value for progression free survival and 102 correlated with overall survival. Hierarchical clustering analysis among the genes related to overall survival revealed two distinct groups with upregulation of genes related to cytokine-cytokine receptor interactions and chemokine signaling pathways linked to better outcomes. Conversely, upregulation of genes related to energetic and metabolic processes were linked to worse overall survival. The trial establishes sunitinib with nivolumab as an active combination with manageable toxicity for the treatment of advanced soft tissue sarcomas.
Kohei Shigeta, Aya Matsui, Hiroto Kikuchi, Sebastian Klein, Emilie Mamessier, Ivy X Chen, Shuichi Aoki, Shuji Kitahara, Koetsu Inoue, Ayako Shigeta, Tai Hato, Rakesh R Ramjiawan, Daniel Staiculescu, Dieter Zopf, Lukas Fiebig, Gabriela S Hobbs, Alexander Quaas, Simona Dima, Irinel Popescu, Peigen Huang, Lance L Munn, Mark Cobbold, Lipika Goyal, Andrew X Zhu, Rakesh K Jain, Dan G Duda
Journal for ImmunoTherapy of Cancer 2020;8:e001435 (24 November 2020)
Research
Summary:
Combination immunotherapy with atezolizumab and the vascular endothelial growth factor (VEGF) antagonist antibody bevacizumab was a major breakthrough in the treatment of hepatocellular carcinoma (HCC). Targeting VEGF with broadly selective tyrosine kinase inhibitors (TKis) such as sorafenib is also a mainstay in HCC treatment, but the potential benefits of combining these small molecules with checkpoint inhibitors remain unknown. In models of HCC in mice with liver damage, Kohei Shigeta and colleagues demonstrated that a combination of anti-PD-1 antibody and the multi-TKi regorafenib led to delayed tumor growth and prolonged survival, but only when given at an intermediate dose (10 mg/kg, not 5 mg/kg or 20 mg/kg). Low dose regorafenib plus PD-1 didn’t slow tumor growth and the high dose didn’t improve survival. The intermediate dose alone promoted vascular normalization and decreased tissue hypoxia. Pharmacokinetic analyses showed that plasma exposure to regorafenib increased in a dose-dependent manner both alone or in combination with the anti-PD-1 antibody, but tumor exposure to the drug was increased in the presence of the immunotherapy. Combination of anti-PD-1 and intermediate dose regorafenib promoted the infiltration of activated CD8+ T cells that produced interferon gamma. RNA Scope in situ hybridization showed that the combination regimen increased expression of CXCL10 in cancer cells and upregulated CXCR3 mRNA in tumor infiltrating lymphocytes. In mice lacking CXCR3, no additional survival benefit was seen with adding regorafenib to anti-PD-1. In samples from human patients with HCC and acute myelogenous leukemia (AML), detectable CXCR10 expression was found in cancer cells, which increased after treatment in those who received regorafenib as a component of standard care. The study provides new insight into the synergy between vascular normalization and checkpoint blockade, laying the groundwork for potential investigation of combination regimens in future trials.
Diana Canals Hernaez, Michael R Hughes, Pamela Dean, Peter Bergqvist, Ismael Samudio, Ola Blixt, Katharina Wiedemeyer, Yicong Li, Chris Bond, Eric Cruz, Martin Köbel, Blake Gilks, Calvin D Roskelley, Kelly M McNagny
Journal for ImmunoTherapy of Cancer 2020;8:e001128 (26 November 2020)
Research
Summary:
Upregulation of podocalyxin is associated with poor outcomes on metastatic tumors, however expression of the protein on healthy vascular endothelia and kidney podocytes limits its utility as a therapeutic target. Reasoning that aberrant post-translational modifications in tumor cells might lead to novel epitopes, Diana Canals Hernaez and colleagues developed an antibody specific for a cancer-restricted glycosylation in the mucin domain on podocalyxin. Using the selected lymphocyte antibody method (SLAM), a potently reactive antibody that recognized podocalyxin on neoplastic cell lines, but not primary endothelial cells, was isolated. The monoclonal antibody that showed the strongest reactivity against podocalyxin on tumor cells, PODO447, was found to be minimally reactive against normal tissue, with lower than 10% positivity on mucosal epithelial cells from human breast, fallopian tube and endometrium. In vitro enzymatic degradations and experiments with truncated versions of the antibody revealed binding within the mucin domain. Screening against a well-characterized array of 320 distinct glycan structures showed that PODO447 exhibited the highest affinity to a rare N-terminal acetylgalactosamine-beta-1 motif on O-linked glycans. When modified with a monomethyl auristatin E payload with a valine-citrulline cleavable linker, the PODO447 vedotin antibody-drug conjugate caused a three-fold reduction in viability of podocalyxin-expressing ovarian cancer cell lines. Immunostaining a tissue microarray that included 219 cases of ovarian cancer with PODO447 revealed that 65.8% (144) were positive for the unique glycoepitope. Reactivity was significantly different across the major histotypes, with only 40% of mucinous carcinomas being PODO447 positive, while a majority of endometrioid (74.1%), clear cell (68.0%), low-grade serous (75.0%) and high-grade serous ovarian carcinoma (65.8%) showed reactivity. The findings validate the concept of tumor-specific glycoepitopes as potential therapeutic targets for further development.