ABSTRACT
Background: SARS-CoV-2 pandemic has deeply modified healthcare seeking and services in Europe since February 2020 with delays in treatment delivery and changes in the standards of care. The organization of cancer centers (CC) has been transformed to minimize virus exposure in cancer patients (pts). Real-time assessment of the impact on cancer outcomes can optimize decision-making for future epidemic episodes. Methods: A discrete-event simulation (DES) model was developed to model individual pt pathways during the pandemic in a context of constrained medical resources. Cancer pt care is modeled based on pandemic-adapted guidelines for medical practice. Pt flow is derived from medico-administrative databases using time series methods to estimate the proportion of punctual / late visits and associated delay and to extrapolate future flows. Finally, the impact of modified care on survival is estimated using literature data. Results: From March to December 2020, based on data from Gustave Roussy CC in France (n= 4877 included pts), estimated overall treatment delay is <= 7 days in 86,6% of pts and 5,2% of pts have a delay higher than 2 months. More than 94% of this duration is delay in pt request for care, causing 99 pts to suffer a major prognosis change upon arrival. Delayed pt flows result in a highly time-variable use of medical resources, with important queues forecast for surgery care and chemotherapy. The handling of such queues will require intensified healthcare professionals effort. Projections show that, in the best-case scenario, ie without a 2nd pandemic wave, treatment delays and modifications will result in around 49 additional 5-year cancer-specific deaths (+ 2,25% of 5-year deaths), mainly in liver, sarcomas and head and neck cancer pts. Conclusions: In a resource-constrained context, optimization of the benefit-risk ratio between COVID-19 and cancer care is key. Simulations of individual projections from actual hospital data, show a 2.25% increase of the 5-year risk of death and that pandemic-related cancer burden is mainly due to patient-induced lateness in seeking care. Defining optimal strategies in terms of screening, monitoring and prioritization for care could minimize the impact of future pandemic episodes. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: A. Bardet: Advisory/Consultancy: Roche. M. Faron: Travel/Accommodation/Expenses: Ipsen;Travel/Accommodation/Expenses: Novartis;Travel/Accommodation/Expenses: Pfizer;Honoraria (self): HRA Pharma;Honoraria (self): Ipsen. I. Borget: Honoraria (self): Merck;Honoraria (self): CSL Berhing;Honoraria (self): Allergan;Honoraria (self): Novartis;Research grant/Funding (institution): BMS. S. Michiels: Advisory/Consultancy: IDDI;Advisory/Consultancy: Janssen Cilag;Honoraria (self), IDMC member: Hexal;Honoraria (self), IDMC member: Steba;Honoraria (self), IDMC member: IQVIA;Honoraria (self), IDMC member: Roche;Honoraria (self), IDMC member: Sensorion;Honoraria (self), IDMC member: Biophytis;Honoraria (self), IDMC member: Servier;Honoraria (self), IDMC member: Yuhan. F. Barlesi: Honoraria (self), further elements to be provided: AstraZeneca;Honoraria (self): Bayer;Honoraria (self): Bristol-Myers Squibb;Honoraria (self): Boehringer-Ingelheim;Honoraria (self): Eli Lilly Oncology;Honoraria (self): F.Hoffmann-La Roche Ltd;Honoraria (self): Novartis;Honoraria (self): Merck;Honoraria (self): MSD;Honoraria (self): Pierre Fabre;Honoraria (self): Pfizer;Honoraria (self): Takeda;Honoraria (institution): AbbVie;Honoraria (institution): Amgen;Honoraria (institution): AstraZeneca;Honoraria (institution): Bayer;Honoraria (institution): Bristol-Myers Squibb;Honoraria (institution): Boehringer-Ingelheim;Honoraria (institution): Eisai;Honoraria (institution): Eli Lilly Oncology;Honoraria (institution): F. Hoffmann-La Roche Ltd;Honoraria (institution): Genentech;Honoraria (institution): Ipsen;Honoraria (institution): Ignyta;Honoraria (institution): Innate Pharma;Honoraria (institu ion): Loxo;Honoraria (institution): Novartis;Honoraria (institution): MedImmune;Honoraria (institution): Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Takeda;Research grant/Funding (institution): AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. J. Bonastre: Honoraria (self): Bristol-Myers Squibb;Advisory/Consultancy: Bristol-Myers Squibb;Advisory/Consultancy: MSD;Advisory/Consultancy: PharmaMar (Inst);Advisory/Consultancy: Bristol-Myers Squibb (Inst);Advisory/Consultancy: Merck Serono;Travel/Accommodation/Expenses: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.
ABSTRACT
Background: Clinical data suggest an aggravated COVID-19 disease course in cancer patients treated with immune checkpoint inhibitors (ICI). European guidelines advise to defer ICI therapy until complete resolution of COVID-19. However, mechanistic insight into how ICI impacts COVID-19 immunopathology is absent. Methods: We performed single-cell RNA- and T-Cell Receptor-sequencing (TCR-seq) on bronchoalveolar lavage fluid of COVID-19 pneumonia (n=19) and non-COVID pneumonia (n=10), and co-analyzed CD8+ T-cells with publicly available tumor-infiltrating T-cell data of treatment-naïve and ICI-treated patients (Sade-Feldman, Cell, 2018;Lambrechts, Nat Med, 2018). Cell lineages were determined by trajectory inference (Slingshot, Monocle v2) and stratified per condition. Pathogen- or tumor-directed T-cells were defined based on clonal selection (Zhang, Nature, 2018). To identify ICI responsive cells, we calculated a score derived from a validated gene set denoting ICI reactivity (Okamura, J. Autoimmun, 2019). Results: We identified 3 CD8+ T-cell lineages, with ‘Naïve’ T-cells transitioning into ‘Effector Memory’ cells and then branching into either ‘Recently Activated Effector Memory (TEMRA)’, ‘Exhausted (TEX)’ or ‘Resident Memory (TRM)’ T-cells. In COVID-19, clonal expansion indicating a SARS-CoV-2 antigen-specific T-cell response, was mainly observed in the highly cytotoxic ‘TEMRA’ lineage. In contrast, tumor-specific T-cells were found in the ‘TEX’ lineage. Of importance, the ICI responsiveness score was significantly higher in the non-pathogen-directed ‘TRM’ and ‘TEX’ cells in COVID-19. In cancer, ‘TEX’ cells were shown to be ICI responsive as expected. [Formula presented] Conclusions: We are the first to provide a mechanistic rationale for an aggravated COVID-19 disease course in ICI-treated patients. Whereas ICI reactivates tumor-directed ‘exhausted’ T-cells in cancer, it preferentially potentiates non-pathogen-directed T-cells in COVID-19, thereby contributing to lung damage without boosting the antiviral immune response. Clinical trial identification: In-depth Immunological Investigation of COVID-19 (COntAGIouS). - Clinical Trial identifier: NCT04327570. - Ethical approval obtained by the Ethics Committee of University Hospitals - KU Leuven. File number S63881. Legal entity responsible for the study: University Hospitals - KU Leuven. Funding: Kom op tegen Kanker (Stand up to Cancer). Disclosure: All authors have declared no conflicts of interest.