PURPOSE: Universal cancer peptide–based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS: A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders ( P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders ( P = .005), respectively. CONCLUSION: UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Background: The positive role of CD8+ tumor-infiltrating lymphocytes (TIL) in patients with colorectal cancer (CRC) has been well described but the prognostic value of CD4 T cell subsets remained to be investigated. In this study, we expanded TIL from surgically resected liver metastases of patients with CRC and characterized the phenotype and the prognostic value of expanded-CD4 T cells. Methods: Liver metastases were surgically resected from 23 patients with CRC. Tumors were enzymatically digested and cultured in high dose of interleukin-2 for up to 5 weeks. T cell phenotype and reactivity of cultured-T cells were measured by flow cytometry and correlated with patients’ clinical outcomes. Results: We successfully expanded 21 over 23 TIL from liver metastases of patients with CRC. Interestingly, we distinguished two subsets of expanded T cells based on T cell immunoglobulin mucin domain-containing protein 3 (TIM-3) expression. Medians fold expansion of expanded T cells after rapid expansion protocol was higher in CD3⁺TIM-3^low cultures. In an attempt to investigate the correlation between the phenotype of expanded CD4 T cells and clinical outcomes, we observed on one hand that the level of Tregs in culture as well as the expression of both PD1 and TIM-3 by expanded T cells was not correlated to the clinical outcomes. Interestingly, on the other hand, cultures containing high levels of Th17 cells were associated with a poor prognosis (p=0.0007). Conclusions: Our data confirmed the presence of Th17 cells in expanded T cells from liver metastases. Among CD4 T cell characteristics investigated, TIM-3 but not programmed cell death protein 1 predicted the expansion capacity of TIL while only the Th17 phenotype showed correlation with patients’ survival, suggesting a particular role of this T cell subset in CRC immune contexture. Trial registration number: NCT02817178.

Breast Cancer (BC) is the most common type of cancer in women around the world and 70% of cases are hormone-receptor positive (HR+). In 40% of cases, a key mechanism of endocrine resistance to the standard first line is a mutation of the ligand-binding domain (LBD) of Estrogen Receptor 1 (ESR1) encoding estrogen receptor α (ER). Most common ESR1 mutations that occur at positions 537 and 538 have been associated with poor clinical outcomes. ESR1 mutations have the potential to provide neoantigens. This study aims to identify if ESR1 mutations generate specific T cell responses against ESR1 neoantigens in patients with HR+ HER2− BC, and to investigate if ESR1 mutations might correlate with a gene expression profile related to immune surveillance disruption. We identified candidate ESR1-derived peptides by predictive software (SYFPEITHI and NetMHCpan 3.0). Then the immunogenicity of ESR1-derived peptides was assessed in Peripheral-Blood-Mononuclear-Cells from 31 healthy donors (HD) and 25 patients with metastatic HR-positive BC by IFN-γ ELISpot assay. A vaccination assay on a humanized mouse model (HLA-A2/DR1) was used to validate the immunogenicity and the presentation of these peptides. Finally, we used Bulk RNA-Seq sequencing along with MCPcounter, a cellular deconvolution method, to investigate the immune contexture of ESR1-mutated BC. Preliminary results showed recognition of ESR1-derived peptides by women HD lymphocytes but not in men. Frequencies and intensities of such immune responses were increased in patients with BC. Our results showed that 40% of patients had specific immune responses. In addition, we demonstrated the HLA-A2 ESR1 peptide immunogenicity in humanized HLA-A2/DR1 mice. In a data set generated from BC patients refractory to conventional therapy we showed that ESR1 mutations are correlated in advanced diseases with downregulation of molecules involved in antigen presentation and with loss HLA Class I gene expression. ESR1-mutated BC had a decrease in immune cell infiltration. These results support that common ESR1 mutations generate neoantigens in hormone-receptor positive metastatic breast cancers. If ESR1 peptides-restricted lymphocytes were detectable in BC patients, ESR1 mutations promote immune escape at advanced stages. ClinicalTrials.gov, NCT02838381. Registered on June 2012.

Purpose: To investigate the immunoprevalence of SALL4-derived peptides in healthy volunteers and cancer patients. Experimental Design: A multistep approach including prediction algorithms was used to design in silico SALL4-derived peptides theoretically able to bind on common HLA-DR and HLA-A/B molecules. The presence of T-cell responses after a long term T-cell assay (28 days) against SALL4 was monitored in 14 healthy donors and the presence of T-cell responses after a short term T-cell assay (10 days) was monitored in 67 cancer patients using IFN-γ ELISPOT assay. A T-cell clone specific for the immunoprevalent A18 K-derived peptide was isolated, characterized and used as a tool to characterize the natural processing of A18 K. Results: A SALL4 specific T-cell repertoire was present in healthy donors (8/14) and cancer patients (29/67) after short term T-cell assay. We further identified two immunoprevalant SALL4-derived peptides, R18 A and A18 K, which bind MHC-class II. In parallel, an A18 K specific Th1 clone recognized monocyte derived Dendritic Cell (moDC) loaded with SALL4 containing cell lysate. The level of IFN-γ secreted by specific T-cell clone was greater in presence of moDC loaded with SALL4 containing cell lysate (49.23 ± 14.02%) than with moDC alone (18.03 ± 3.072%) (p = 0.0477) Conclusion: These results show for the first time immunogenicity of SALL4 oncogenic protein-derived peptides, especially A18 K and R18 A peptides and make them potential targets for personalized medicine. Thus, SALL4 possess major characteristics of a tumor antigen.

Since 2007, a new class of biologic products for human use called “advanced therapy medicinal products (ATMP)” have been legally integrated in the European Medical Agency. They consist of recombinant nucleic acid, engineered cells, cells, or tissues. In the United States, ATMP fall under the regulatory framework of biological products and the term “cell and gene therapy product” is used in the legislative and regulatory documents. Potential clinical applications are broad, particularly, in the field of cancer, inherited genetic disease, and regenerative medicine. Indeed, the benefit conferred by CD19 chimeric antigen receptor T cells led to the first engineered cell therapy products to be approved by the Food and Drug Administration (FDA) in 2017. Gene therapy products to treat orphan diseases are also extensively developed with many clinical trials ongoing in the world. Nevertheless, the use of these therapeutic products is complex and requires careful considerations in the terms of regulatory and hospital setting requirements, such as storage, handling, administration, and disposal which justify the implementation of a secured medication circuit. Through this systematic review of the literature, the authors wanted to compile data on the assessment of environmental exposure related to the use of ATMP in healthcare setting to secure their medication circuit. A literature search was conducted on PubMed and Web of Science, and 32 publications dealing with environmental exposure assessment and ATMP were selected. In addition, marketed ATMPs were identified and data regarding the environmental concerns were extracted from product information sections from European Public Assessment Reports (EPAR). The environmental contamination assessments were mainly addressed in the reviews rather than in original articles related to the use of ATMP. Most of the product information sections from EPAR suggested precautions rather than requirements when dealing with environmental consideration following ATMP handling. Nevertheless, these precautions usually remain elusive especially concerning waste disposal and the detection of biological material on the work surfaces, and mainly relate to the genetically modified organisms (GMO) over non-GMO cellular products. Pharmaceutical oversight and adherence to the good preparation practices and good clinical practices are essential to ensure the safe use in term of environmental concern of these new therapeutic products in healthcare setting.

Background. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. Methods. We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. Results. Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points between days 1 and 29. Improvement in the WHO-CPS and the SOFA score were observed in 83.5% and 79.3% of patients, respectively, from day 10. However, there was no effect of remdesivir on the 90-day survival based on the control cohort for hospitalized COVID-19 patients with invasive ventilation. Conclusions. SOFA score appeared to be an attractive approach to assess remdesivir efficacy and stratify its utilization or not in critically ill patients with COVID-19. This study brings a new clinical benchmark for therapeutic decision making and supports the use of remdesivir for some hospitalized COVID-19 patients.