Fast Clearance of the SARS-CoV-2 Virus in a Patient Undergoing Vaccine Immunotherapy for Metastatic Chordoma: A Case Report

The emergence of the SARS-CoV-2 virus has been associated with perplexing clinical sequelae and phenomena that often have no clear link to the underlying infection. There is a wide spectrum of symptoms associated with infection, from minimal respiratory complaints to severe multi-organ failure, often resulting in death. Individuals with malignancies, particularly those whose treatments have left them immunocompromised or immunosuppressed, are among the patient populations thought to be at greater risk for more severe illness. A man with aggressive metastatic chordoma contracted the SARS-CoV-2 virus and was diagnosed with COVID-19 while undergoing intravenous brachyury vaccine immunotherapy. His disease course was remarkably mild, and the virus cleared rapidly. Despite a treatment delay of 3 months due to the COVID-19 pandemic, the patient's disease has been stable and tumor-related pain has significantly improved. This suggests not only an intact, functional immune system, but also one that appears to have been responsive to cancer treatment. It has been suggested that individuals undergoing treatment for metastatic cancer are at greater risk of severe SARS-CoV-2-related illnesses and complications. While immunosuppression may be a problem, particularly in those receiving conventional chemotherapeutic agents, it is possible that the non-specific effects of immune-enhancing therapies may confer some protection against SARS-CoV-2

Characterizing the potency and impact of carbon ion therapy in a primary mouse model of soft tissue sarcoma

Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared to X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to post-treatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 days and 28.1 days, and 0.060 mm3/day and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X-rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications

A phase 1 open label trial of intravenous administration of MVA-BN-Brachyury vaccine in patients with advanced cancer

Abstract only 2617 Background: Brachyury is a member of the T-box family of transcription factors which is overexpressed in several tumor types and has been associated with treatment resistance, epithelial to mesenchymal transition and metastatic potential. MVA-BN-Brachyury vaccine is a vector-based therapeutic cancer vaccine which demonstrated immunogenicity and safety in previous clinical trials. Preclinical studies suggested that IV administration of vaccines can induce superior CD8 + T-cell responses as compared with SC or IM routes. This is the first-in-human study to evaluate safety and tolerability of IV administration of this vaccine. Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with MVA-BN-Brachyury vaccine in a phase 1, open-label, 3+3 dose-escalation study. Eligible patients received a total of three vaccine doses intravenously Q3W at 1x10 7 (DL1), 1x10 8 (DL2), or 1x10 9 infections units (Inf.U) (DL3). Patients were admitted for 48 hours for observation after each dose and had imaging at baseline and 1 and 3 months after the last vaccine dose. Primary objective was to determine the safety and tolerability and establish the recommended phase 2 dose (RP2D). Immune assays were performed in the first 10 enrolled patients. Results: In 13 patients (10 chordoma, 1 small cell breast, 1 prostate, 1 colorectal cancer), no dose-limiting toxicities were observed. Right upper quadrant abdominal pain was the only grade 3 TRAE. All other TRAEs were grade 1 or 2; most common was cytokine release syndrome (four grade 2 and one grade 1. As of Feb 2021, 9 patients completed treatment and two planned restaging scans: 5 patients had PD (3 in DL1 and 2 in DL2), 3 had SD (2 in DL2 and 1 in DL3) and 1 had PR (DL3) as their best treatment response per RECIST 1.1. One patient with advanced sacral chordoma had significant reduction of ulcerated skin metastases after 2 doses, followed by 33% shrinkage at the end of trial. Two chordoma patients with SD reported significant pain improvement. Multifunctional Brachyury, CEA, and MUC1 specific T cells were increased after vaccination in in 60%, 67%, and 50% of patients, respectively. Conclusions: MVA-BN-Brachyury IV vaccine is safe across all tested dose levels and suggesting activity in chordoma at DL3 for which this vaccine was granted FDA orphan drug designation. Mild cytokine release syndrome (rigors, chills, fever and hypotension) has been observed in 5 patients and managed with IV fluids and steroids in 2 patients. A dose 1 x 10 9 Inf.U (DL3) was selected for RP2D based upon available safety data. Further research is pending to evaluate clinical benefit and immunogenicity. Clinical trial information: NCT04134312

Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer

MVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8 T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM. Between January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose. No dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens. Intravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 10 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose. NCT04134312