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CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.

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.

In the context of regenerative endodontics research with the development of biomaterials, this work aimed to develop and test a prototype biomimetic bioreactor of a human tooth. The bioreactor was designed to reproduce a shaped dental canal connected with a cavity reproducing the periapical region and irrigated through two fluidic channels intended to reproduce the apical residual vascular supply. A test biomaterial composed of polylactic acid/polycaprolactone-tannic acid (PLA/PCL-TA) was produced by electrospinning/electrospraying and calibrated to be inserted in a dental canal. This biomaterial was first used to evaluate its imbibition capacity and the oximetry inside the bioreactor. Then, Dental Pulp Stem Cells (DPSCs) were cultured on PLA/PCL-TA cones for 1-3 weeks in the bioreactor; afterward cell adhesion, proliferation, and migration were histologically assessed. Complete imbibition biomaterial was obtained in 10 min and oximetry was stable over time. In the bioreactor, DPSCs were able to adhere, proliferate and migrate onto the surface and inside the biomaterial. In conclusion, this bioreactor was used successfully to test a biomaterial intended to support pulp regeneration and constitutes a new in vitro experimental model closer to clinical reality.

The clinical benefit of pharmaceutical cares in improving the quality-of-care outcomes is well demonstrated. Clinical pharmacy services are not systematically deployed in cancer units in the absence of economic data. The aim of this prospective, observational 1-year study was to evaluate the clinical, economic and organisational impacts of pharmaceutical care into a multidisciplinary day hospital for patients treated with oral cancer drugs.All pharmacists' interventions (PI) were documented and their impact and the probability of adverse drug events were assessed using the clinical, economic and organisational tool.Among 360 admissions, an average of 1.81 PI per admission was accepted. Among 452 PI leading to a clinical benefit on the patient, 16.9% had a major impact, and 1.9% had an impact on survival. The large majority of PIs (87%) increased the quality-of-care organisation. The budget impact model showed a total cost savings and cost avoidance of €539,047 per year and a cost-benefit ratio of 7.07:1. The direct cost-benefit was €201,741, and the cost avoidance was €337,306.Multidisciplinary care and pharmaceutical care are key elements to improve cancer patients' outcomes and avoid evitable healthcare costs.

Kidney transplant recipients (KTR) are at increased risk for COVID-19-associated complications. We aimed to describe the evolving epidemiology and outcome of PCR-documented SARS-CoV-2 infection in KTR followed at our institution from March 2020 to May 2022. The primary endpoint was hospitalization for COVID-19-related symptoms or death within 28 days from diagnosis. Overall, 243 cases were included of which 68 (28%) developed the primary outcome. A significant decrease in the incidence of the primary outcome was observed (p < 0.001, r −0.342) during the study period. Anti-Spike monoclonal antibodies (mAbs) were administered as early treatment (within 5–7 days of onset of symptoms) in 101 patients (14 with casirivimab/imdevimab and 87 with sotrovimab). Among 145 patients who had received at least one vaccination dose before infection, 109 patients were considered as adequately vaccinated. Multivariate analysis revealed that the Charlson Comorbidity Index (P 0.001; OR 1.28, CI 1.11–1.48) was associated with the primary outcome, while early administration of mAbs (P 0.032; OR 0.39, CI 0.16–0.92) was associated with a better outcome, but not infection during the period of the omicron variant predominance or adequate vaccination.

International audience; No abstract available

Scientific advances in the last decade have highlighted the use of immunotherapy, especially immune checkpoint inhibitors, to be an effective strategy in cancer therapy. However, these immunotherapeutic agents are expensive, and their use must take into account economic criteria. Thus, the objective of the present study was to systematically identify and review published EE related to the use of ipilimumab, nivolumab or pembrolizumab in melanoma, lung cancer, head and neck cancer or renal cell carcinoma, and to assess their quality. The systematic literature research was conducted on Medline via PubMed and the Cochrane Central Register of Controlled Trials to identify economic evaluations published before July 2018. The quality of each selected economic evaluation was assessed by two independent reviewers using the Drummond checklist. Our systematic review was based on 32 economic evaluations using different methodological approaches, different perspectives and different time horizons. Three-quarters of the economic evaluations are full (n = 24) with a Drummond score ≥ 7, synonymous of “high quality”. Among them, 66% reported a strategy that was cost-effective. The most assessed immunotherapeutic agent was nivolumab. In patients with renal cell carcinoma or head and neck cancer, it was less likely to be cost-effective than in patients with melanoma or lung cancer. Whether or not these findings will be confirmed remains to be seen when market approval to cover more indications is extended and new effective immunotherapeutic agents become available.

Background Cancer patients are considered highly vulnerable to the COVID-19 pandemic. However, delaying cancer-specific therapies could have a deleterious effect on survival. The potential suppressive effects of chemotherapies or cancer-related microenvironment raised the question on how cancer patients’ immune system responds to SARS-CoV-2 virus. Methods We have started a prospective monocentric trial entitled COV-CREM (NCT04365322) in April 2020. The primary objective of the trial was to assess specific immune response's intensity and diversity to SARS-CoV-2 in infected patients. Results In this study, we showed that cancer patients (28 solid tumours, 11 haematological malignancies) exposed to SARS-CoV-2 produced a high rate of specific antibodies, as observed in patients without a cancer history (n = 29). However, our results highlight a lack in the generation of T-cell responses against CoV–N, M and S proteins from the SARS-CoV-2 virus, suggesting that cancer patients failed to mount a protective T-cell immunity. Nevertheless, SARS-CoV-2 infection did not impair established immune memory since specific responses against common viruses were not hampered in cancer patients. Conclusion Given the severity and the unknown evolution of the ongoing COVID-19 pandemic, it is of fundamental importance to integrate cancer patients in vaccination programs.

Introduction Influenza vaccination coverage currently remains below the 75% recommended threshold by the World Health Organization. To correct this situation, experiments have been successively carried out in France to enable community pharmacists to vaccinate at-risk populations. In this context, a study was conducted with pharmacists from the French Franche-Comte region to evaluate their positioning, needs and expectations regarding influenza vaccination at community pharmacies. Materials and methods A survey was created and sent to licensed pharmacists in March of 2018. This consisted of 4 parts: characteristics of the community pharmacy; positioning of the pharmacist regarding vaccinations carried out at the pharmacy; training needs and expectations; and willingness to implement vaccinations. Results The participation rate in this survey was 32% (137/427). More than 90% of the pharmacists agreed that community pharmacies’ assets were adequate for the implementation of these vaccinations (accessibility and availability), although 52% considered this complicated. Their main fears were reluctance from patients and conflicts of interest with other health professionals authorized to vaccinate (58%). The needs and expectations regarding pharmacy student training were essential for 94% of them as well as continuous training of practicing pharmacists (96%). The willingness of pharmacists to vaccinate stemmed from the fact that influenza vaccination coverage would increase for at-risk subjects (36%). Conclusion This survey allowed us to assess the favorable positioning and the real interest of pharmacists from Franche-Comte regarding the influenza vaccination done at community pharmacies, given the proviso that they were given relevant training and allocated adequate resources.

International audience; Adaptive Immune responses generated by SARS-CoV-2 virus in convalescent patients according to disease severity remain poorly characterized. To this end, we designed a prospective study (NCT04365322) that included 60 COVID-19 convalescent patients (1-month post infection) in two cohorts respectively entitled mild illness and severe pneumonia. The monitoring of peripheral immune responses was performed using IFNᵧ ELISpot assay. The serology index of each patient was investigated at the same time. Patients with severe pneumonia were older and had more comorbidities than patients with mild illness. T-cell responses in term of frequency and intensity were clearly distinct between mild illness and severe pneumonia patients. Furthermore, our results demonstrated that recent history of COVID-19 did not hamper viral memory T-cell pool against common viruses (Cytomegalovirus, Epstein-Barr-virus and Flu-virus). The presence of potent adaptive immunity even in patients who underwent severe pneumonia sustain the rationale for the development of protective therapeutics against SARS-CoV-2.

The transition to oral therapies in patients with multiple myeloma (MM) offers potential benefits to patients; however, they must self-manage their medication and adherence plays an important role in patient care. It has been shown that patient satisfaction with their medication has a strong positive correlation with adherence in chronic diseases. The aim of this study was to estimate adherence rate of oral antimyeloma therapies and to identify risk factors for medication non-adherence. This observational, prospective, and multicentre survey based on a self-report questionnaire enrolled MM patients with at least 3 months of oral therapy. The 6-item Girerd scale and the medication possession ratio (MPR) were used for measuring medication adherence and the SATMED-Q® questionnaire was used for measuring satisfaction. An analysis of risk factors for non-adherence to oral therapy was performed using univariate analysis. A total of 101 patients participated in the survey, yielding a response rate of 87%. The prevalence of adherence to oral antimyeloma therapy was estimated at 51.5% using the Girerd questionnaire. According to the MPR, adherence was evaluated at 96% (i.e. MPR ≥ 0.80). Both methods combined, adherence was estimated at 50.5%. One risk factor for medication non-adherence was identified: Eastern Cooperative Oncology Group Performance Status > 2 (p = 0.007). One predictive factor for high medication adherence was identified: high satisfaction with treatment (p = 0.01). Identifying patients at higher risk for non-adherence allows clinical pharmacists to personalise therapeutic information and education and to improve the quality of healthcare overall.

International audience

BackgroundThe 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.MethodsLiver 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.ResultsWe 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-3low 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).ConclusionsOur 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 numberNCT02817178.

Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.

Resume Introduction La prise en charge de la douleur est un enjeu de sante publique important, particulierement en cancerologie. Dans une demarche d’evaluation des pratiques professionnelles, l’IRFC-FC a realise une enquete chez des patients presentant une tumeur solide metastatique osteophile en Franche-Comte. Les objectifs etaient d’evaluer la prevalence de la douleur, ses caracteristiques, sa prise en charge et son impact sur la qualite de vie. Methode Une enquete observationnelle, prospective et multicentrique a ete realisee via un questionnaire d’autoevaluation. Ont ete inclus les patients presentant un cancer metastatique du sein ou de la prostate pris en charge dans 5 hopitaux de jour de l’IRFC-FC sur une periode de 3 mois. Resultats Deux cent trente-trois questionnaires ont ete analyses. La prevalence de la douleur etait de 48,5 %. Trois-quarts des patients algiques avaient une douleur chronique de fond, d’intensite moderee a severe, associee ou non a des acces douloureux. Eu egard a l’intensite de leur douleur et a leur traitement antalgique, 42,0 % des patients semblaient sous-traites. Quatre-vingt-cinq pour cent des patients traites declaraient etre observants et estimaient que leur douleur etait bien prise en charge malgre un impact negatif sur la qualite de vie. Conclusion La mise en œuvre d’un chemin clinique est essentielle pour garantir une prise en charge standardisee, optimale et efficiente des patients algiques. L’evaluation de la satisfaction des soins et de la qualite de vie doit etre integree a la pratique clinique pour mieux identifier les patients algiques dont le traitement est inadapte.

Background Anal squamous cell carcinoma (SCCA) is associated with E6 and E7 oncoproteins encoded by human papillomavirus (HPV) 16. Addition of Docetaxel to 5-Fluorouracil plus Cisplatin (DCF) induces favorable disease control and complete remission rate in recent clinical trials. Taking this observation into account, we decided to analyze the impact of DCF chemotherapy on adaptive immunity and immunosuppressive cells in SCCA. Methods Peripheral blood mononuclear cells from healthy donors and SCCA patients included in Epitopes-HPV01 and 02 studies were analyzed. The presence of T-cell responses after short term T-cell stimulation against HPV16-E6/E7 and TERT-antigens was measured by IFNγ-ELISpot. Immune checkpoint expression and immunosuppressive cells were monitored by flow cytometry. Results We first observed an enhanced HPV-specific T-cell response following DCF chemotherapy. Our investigations also suggest that TERT might be a relevant antigen in HPV-driven cancers. TERT-restricted CD4 Th1 were correlated to E6 responses and also enhanced following DCF treatment of SCCA patients. The distribution of T-cell exhaustion markers on peripheral T lymphocytes unraveled a drop of CD226 expression and the emergence of CD226-TIGIT+ T-cell subset. Monocytic-myeloid-derived-suppressor cells (M-MDSC) and regulatory T-cell (Treg) rates were increased. Treg levels and T-cell exhaustion markers did not influence clinical outcomes and frequencies of specific immune responses. M-MDSC levels monitored after DCF chemotherapy were correlated with progression free survival and antigen-specific T-cell response intensity and diversity. Conclusions DCF chemotherapy did not impair antigen-specific T-cell responses, supporting the potential interest to combine DCF chemotherapy with immunotherapies. Moreover, our study identifies post-therapy M-MDSC as a prognostic factor in SCCA patients. Clinical trial identification Epitopes-HPV01: NCT01845779 Epitopes-HPV02: NCT02402842. Legal entity responsible for the study University Hospital of Besancon. Funding Besancon University Hospital, Ligue Contre le cancer Grand-Est and Association Nationale de la Recherche et de la Technologie. Disclosure All authors have declared no conflicts of interest.

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.

Pain management is a major public health problem, especially in oncology. In order to assess professional practice, the IRFC-FC conducted a survey amongst patients with metastatic osteophilic solid tumor in Franche-Comté. The aims were to assess the pain prevalence, and its characteristics, its management and its impact on patients' quality of life in patients in pain.An observational, prospective and multicenter survey was conducted using a self-report questionnaire. Patients with metastatic breast or prostate cancer managed in 5 day-hospitals of the IRFC-FC over a period of three months were included.Two hundred thirty-three questionnaires were analyzed. Pain prevalence rate was 48.5%. Three quarters of patients in pain had chronic background pain, moderate to severe, with or without breakthrough pain. Considering their pain intensity and their analgesic therapy, 42.0% of patients seem to have an inadequate treatment. Eighty-five percent of treated patients reported to be compliant and felt that their pain was well managed despite a strong impact on their quality of life.The setting of a specific clinical pathway is essential to secure the standardized, optimal and efficient management of patients in pain. The assessment of patient satisfaction and quality of life must be integrated in clinical practice to identify patients in pain for which the treatment is inappropriate.