T-cell mediated response to emerging COVID19 strains in patients with cancer studied via deep learning

Cancer patients, particularly those receiving B cell-depleting therapy for lymphoid malignancies, are at risk of prolonged SARS-CoV-2 infection, poorer clinical outcomes, and delayed initiation or disruption of cancer-directed therapy (Lee at al., 2022, Clark et al., 2021). We first studied T-cell mediated response to the Wuhan strain of SARS-CoV-2 in a cohort of 69 patients with hematologic and solid cancers, including 18 patients who received prior B-cell depleting therapy. Patients with prolonged COVID-19 clearance, defined by a positive PCR test for longer than 30 days, had a broad but poorly converged CD8+ dominant response and a lacking CD4+ response. To conduct this analysis, we performed bulk T-cell receptor (TCR) sequencing of 121 blood samples and tracked over time TCR repertoire statistics such as clonality, convergence, breadth, and depth of COVID-19-associated TCRs during the active and convalescent periods of COVID-19 infection. These SARS-CoV-2-associated TCRs were identified leveraging immunoSEQ T-MAP database (Snyder et al., 2020), a set of TCR sequences derived from COVID-19 patients and experimentally identified as responsive to MHC Class I and II epitopes from the Wuhan SARS-CoV-2 strain using the multiplex identification of TCR antigen assay (Klinger et al., 2015). To extend our TCR repertoire analysis to other SARS-CoV-2 variants, including Omicron, we developed a deep learning (DL) method to predict TCR specificities for new SARS-CoV-2 epitopes. This DL approach also permits the identification of SARS-CoV2-responsive TCRs private to an individual. Combining this DL approach with our TCR statistics methodology, we studied the dynamics of T-cell response to COVID-19 vaccinations in a cohort of 50 patients with cancer and analyzed TCR repertoire characteristics associated with different degrees of COVID-19 severity in a cohort of 42 cancer patients who contracted the Omicron. Understanding cellular response to novel infections is critical for patient care in the context of cancer, and our novel DL-based approach can leverage existing datasets to analyze and track response to emerging viral strains.

Evaluation of the Updated French Autorisation D'Acces Precoce (AAP) Early Access Authorization Pathway

Objectives: To evaluate products reviewed by the Transparency Committee (TC) of the Haute Authorite de Sante (HAS) under the Autorisation d'Acces Precoce (AAP) Early Access Authorization (EAA) pathway and investigate any trends. Method(s): All 97 AAP submissions are publicly available from HAS and were evaluated on or before January 4th, 2023. The TC's opinion was reviewed to obtain the outcome, decision date, therapeutic area, and reasons for rejection. Results were tabulated and descriptive statistics were compiled. Result(s): In total, 79 of the 97 (81%) submissions evaluated were approved for EAA, including renewals of previously granted authorization (6 of 79);18 were rejected. Of the 97 submissions, 35% were indicated for the treatment of solid cancers, 14% for haematological cancers, 10% for ultra-rare diseases, 10% for infectious diseases, 4% for rare diseases, 4% for autoimmune diseases, 4% for skin diseases, and 2% for weight management. Notable approved submissions including those indicated for rare diseases, cancer, autoimmune diseases, and COVID-19, with 93%, 90%, 75%, and 63% of these submissions being granted EAA, respectively. Across the 18 unsuccessful submissions, the main reasons cited for rejection were insufficient efficacy and safety data (78%), lack of innovation compared to existing treatment options (61%), the availability of existing treatment options (56%), and the treatment not being rare enough to qualify for special consideration (28%). Conclusion(s): Since its inception in July 2021, the AAP has proven to be a popular program. As awareness of the program grows and more information becomes available about its benefits and eligibility criteria, it is likely that the number of submissions will continue to increase. However, given the link between submission success and the quality of available data (including a data collection plan), it is recommended manufacturers provide robust evidence to bolster their submissions.Copyright © 2023

Comprehensive medication management services provided via telehealth or hybrid models: A scoping review

Comprehensive medication management (CMM) is increasingly provided by health care teams through telehealth or hybrid modalities. The purpose of this scoping literature review was to assess the published literature and examine the economic, clinical, and humanistic outcomes of CMM services provided by pharmacists via telehealth or hybrid modalities. This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews. Randomized controlled trials (RCTs) and observational studies were included if they: reported on economic, clinical, or humanistic outcomes;were conducted via telehealth or hybrid modalities;included a pharmacist on their interprofessional team;and evaluated CMM services. The search was conducted between January 1, 2000, and September 28, 2021. The search strategy was adapted for use in Medline (PubMed);Embase;Cochrane;Cumulative Index to Nursing and Allied Health Literature;PsychINFO;International Pharmaceutical s;Scopus;and grey literature. Four reviewers extracted data using a screening tool developed for this study and reviewed for risk of bias. Authors screened 3500 articles, from which 11 studies met the inclusion criteria (9 observational studies, 2 RCTs). In seven studies, clinical outcomes improved with telehealth CMM interventions compared to either usual care, face-to-face CMM, or educational controls, as shown by the statistically significant changes in chronic disease clinical outcomes. Two studies evaluated and found increased patient and provider satisfaction. One study described a source of revenue for a telehealth CMM service. Overall, study results indicate that telehealth CMM services, in select cases, may be associated with improved clinical outcomes, but the methods of the included studies were not homogenous enough to conclude that telehealth or hybrid modalities were superior to in-person CMM. To understand the full impact on the Quadruple Aim, additional research is needed to investigate the financial outcomes of CMM conducted using telehealth or hybrid technologies.Copyright © 2022 Pharmacotherapy Publications, Inc.

Anti-S-Rbd Titer and Risk of Clinical Progression in Patients with Covid-19 Pneumonia

Background: Antibodies (Ab) against the receptor-binding-domain of the spike protein (anti-S-RBD) elicited by SARS-CoV-2 infection or vaccination are deemed to be a correlate of protection. We aimed at assessing whether anti-S-RBD titer is associated with the outcome of subjects hospitalized with COVID-related pneumonia. Method(s): Adults hospitalized between Jul 2021 and Jul 2022 for COVID-19 with respiratory failure (SpO2 < 93% on room air) or radiological evidence of pneumonia were included if anti-S-RBD titer was measured within 72h of admission. Time between admission and death/need for intubation was described using Kaplan-Meier curves. Cox Regression analysis, stratified by vaccination status, was used to explore the association between anti-S-RBD titer and survival. Age, gender, days since symptom onset, immunosuppressive conditions and use of monoclonal Ab (mAb) were explored as possible confounders. Result(s): 534 patients were enrolled. Their mean age was 71 years, 63% were male and 61% vaccinated;42% had >=1 immunosuppressive condition among hematological or solid malignancy, HIV, diabetes, end-stage renal failure, liver cirrhosis, organ transplant or immunosuppressive treatment. Antibody titer was significantly higher among vaccinated than among unvaccinated patients (1166 vs 158 BAU/ml;p< 0.001). Among vaccinated subjects, lower titer of anti-S-RBD were measured among those with hematological malignancies (1282 vs 471 BAU/mL;p< 0.001) or who were receiving immunosuppressive therapy (1287 vs 537 BAU/ml;p< 0.001). Older age, shorter time between onset of symptoms and hospitalization and immunosuppressive conditions were associated with higher rates of death or intubation (Fig 1). Using Cox regression stratified for vaccination, a significant association between anti-S-RBD titer and risk of death/intubation was observed (per log2 BAU/ml increase, HR 0.93;95%CI 0.88-0.99;p=0.020), independently of age (per year increase, HR 1.03;95%CI 1.01-1.04), male gender (HR 1.00;95%CI 0.70-1.42) and presence of immunosuppressive conditions (HR 1.46;95%CI 1.01-2.10). Adjustment for mAb treatment did not change the results to a significant Extent. Conclusion(s): Low anti-S-RBD titer was associated with poor outcome among patients hospitalized for COVID19-related pneumonia, regardless of vaccination. In addition, older age and presence of immunosuppressive conditions remain important predictors of mortality. Kaplan-Meier Curves for intubation-free survival according to age, days from symptoms' onset, presence of immunosuppressive conditions and anti-S-RBD titer. (Figure Presented).

Treating Lymphoma in the Pandemic Era: What We Learned from Our Experience at Fondazione Irccs Istituto Nazionale Dei Tumori

From March 2020 to May 2022, when SARS-CoV2 pandemic started spreading in Italy, 15 consecutive patients with non-Hodgkin Lymphoma (NHL) have been treated at the Pediatric Unit of Fondazione IRCCS Istituto Nazionale dei Tumori. Three of 15 patients developed COVID19 while on treatment [1 Burkitt lymphoma (BL), 1 anaplastic large cell lymphoma, 1 lymphoblastic T-cell lymphoma (T-LL)] and one patient at diagnosis [gray zone lymphoma (GZL), previously misdiagnosed as Hodgkin lymphoma]. Median age at diagnosis was 12 years;3 were male. Median positivity time of the nasal swab was 58 days (range 9-107 days). All patients remained asymptomatic or paucisymptomatic (flu-like symptoms) while positive. The first positive patient with T-LL, was in the induction phase of the Euro-LB-02 protocol guidelines: he succeeded in completing the whole treatment during the 107 days of swab positivity, experiencing mild toxicities (grade 2 transaminases and grade 3 lipase increase, both reversible) without significant delays. For this reason, we reduced the total dose of the first HD-MTX (protocol M) and administer the subsequent doses in 6 hours infusion instead of 24 with no further toxicities. After this first experience, all the subsequent patients have been treated accordingly, without major deviations from the established protocols. Minor precautions: the patient with refractory GZL received IEP course instead of IGEV as second-line treatment to avoid severe subsequent immunosuppression;the patient with BL omitted the fourth course of Rituximab during the period of swab positivity. Overall, we did not observe outstanding toxicities except for a toxic MTX level with subsequent reversible acute renal failure. Main teaching from these pilot experiences, which may translate into guidelines: 1) SARS-CoV2 infection is not an absolute contraindication to the oncological treatments. This is of main importance for the patients affected by lymphoma whose dose-intensity has a prognostic value. 2)We need to pay caution during HD-MTX treatment;indeed, we observed unexpected similar toxicities in other patients treated with HD-MTX for other solid malignancies. 3) The clearance of SARS-CoV2 might be exceptionally prolonged with persistent positivity of the nasal swabs for a longer time than the matched healthy population due to the immunosuppression characterizing lymphoma patients. For this reason and given the importance of maintaining the dose-intensity, specific treatments aiming at speeding up the clearing process are warmly suggested. (Figure Presented) Figure 1: (: 091) ITHACA study design and blood sampling time points. (OHT = Orthotopic Heart Transplant).Copyright © 2022 Elsevier Ltd. All rights reserved.

Evaluation of the EUROIMMUN Aspergillus antigen immunoenzyme assay in serum and bronchoalveolar lavage fluid samples

Introduction: The most widely used marker for the diagnosis of invasive aspergillosis (IA) is the detection of galactomannan by ELISA. This study describes the evaluation of the results obtained by Euroimmun Aspergillus antigen ELISA (EIA-GM-E) in serum samples and bronchoalveolar lavage fluid (BAL) from patients at risk of IA, and compares these results with those obtained by Bio-Rad Galactomannan EIA (EIA-GM-BR). Method(s): Anonymous retrospective case-control comparative study in 64 serum samples and 28 BAL from 51 patients. Result(s): Overall agreement of the results of the two assays was observed in 72 of 92 samples (78.3%). The sensitivity of EIA-GM-BR and EIA-GM-E in serum samples was 88.9% and 43.2%, respectively, and 100% and 88.9% for BAL. The specificity of EIA-GM-BR and EIA-GM-E in serum samples was 91.9% for both assays, and 68.4% and 84.2% in BAL. There were no statistically significant differences in the results of both assays. Conclusion(s): Both methods show good results for the discrimination of patients with IA when BAL is tested, or serum in case of EIA-GM-BR.Copyright © 2021 Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica

Hospital-onset COVID-19 and antivirals

Aim: The PINETREE study showed benefit of remdesivir in non-hospitalised COVID patients. This became the evidence base for the NHSE policy on antivirals use in hospital-onset COVID patients. However, there are differences between PINETREE inclusion criteria and NHSE policy eligibility criteria, and PINETREE was conducted when Delta was dominant. We describe attributes, risk stratification and outcomes in hospital-onset COVID patients when Omicron is dominant. Method(s): A retrospective analysis of patients testing COVID +ve post-admission over 30 days at two district hospitals, collecting risk factors as defined by the QCovid model, and outcomes including days on/off oxygen, survival/discharge at 28 days, and whether antivirals were considered/given. Result(s): 68 eligible cases were identified. CV followed by respiratory diseases were the commonest risk factors. In the 28 days after a +ve test, 31% required supplemental oxygen and 16% died. Being male, and having CV disease, active solid malignancy and recent chemo/radiotherapy were over-represented in patients who died. Supplemental oxygen was associated with significantly higher 28-day mortality risk (43% v 4.3%). Average age of those who died was higher than the overall cohort (84 v 75y). 28-day mortality rates for those who received 1, 2 and 3 COVID vaccines were 60%, 21% and 5% respectively. 18 patients met criteria for highest risk group and were eligible for antivirals. Only 11% were considered for antivirals. Conclusion(s): Despite the milder omicron variant and high vaccination rate, hospital-onset COVID is associated with worse outcomes compared to community clinical trials. The lack of antivirals use according to NHSE criteria should push MDTs to consider a validated risk model for antivirals use.

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

Therapeutic delivery: industry update covering January 2022

This industry update covers the period from January 1 through January 31, 2022, and is based on information sourced from company press releases, scientific literature, patents and news websites. January 2022 saw Janssen and Midatech expand their collaboration on bioresorbable polymer microsphere technology for drug delivery. Takeda announced its plans to acquire UK-based Adaptate Biotherapeutics and Gandeeva raised further investment funds to support its drug discovery and development platform focused on the evaluation of protein-drug interactions. Biogen announced that it will sell its stake in a biosimilars joint venture and ABL Bio and Sanofi announced a collaboration around a novel treatment for Parkinson's disease. New regulatory announcements this month included US FDA approvals of a new insomnia treatment for Idorsia and a treatment for atopic dermatitis developed by Pfizer. Insulet gained FDA clearance for a closed-loop insulin pump and Ascendis Pharma followed up its United States approval last year for a once-weekly treatment for growth hormone deficiency with European approval. Pfizer and Ionis announced the discontinuation of the clinical development of a novel cardiovascular drug. In terms of collaborations, Novartis and Alnylam announced they will work together to explore targeted therapies to restore liver function;Scorpion Therapeutics partnered with AstraZeneca to develop novel cancer treatments and Nutriband Inc. and Kindeva Drug Delivery will work together to develop a transdermal fentanyl patch. Collaborations were also announced between Century Therapeutics and Bristol Myers Squibb and Lilly and Entos Pharmaceuticals in the areas of stem cell therapies for cancer treatment and neurology, respectively. A team from the Massachusetts Institute of Technology reported progress in developing oral mRNA treatments and West Pharmaceutical Services published a blog describing the development of a proof-of-principle system for a closed-loop feedback system targeting opioid overdose. A report on the BBC website highlighted the benefits of more sustainable inhalers.

COVID-19 Syndrome After Liver Transplant: Immunosuppression Role and Risk Factors for Mortality

Purpose: Data on mortality and immunosuppression role regarding Liver transplant recipients affected by COVID-19 are still under debate. The present study identified risk factors for mortality and the role of immunosuppression in COVID-19 liver transplant recipients. Method(s): A systematic review about SARS-CoV-2 infection in liver transplant recipients was performed. The primary outcomes were risk factors of mortality and the role of immunosuppression. A meta-analysis was not performed as there was different metric of the same outcome (mortality). Result(s): An overall 1.110 LT recipients of 1.810 SOT were included and data on mortality were available for 1.110 liver transplant recipients with SARS-CoV-2 infection. The mortality rate ranged between 0-37%. Risk factors of mortality were age>60, Mofetil Mycophenolate use, extra-hepatic solid tumor, Charlson Comorbidity Index, male sex, dyspnoea at diagnosis, higher baseline serum creatinine, congestive heart failure, chronic lung disease, chronic kidney disease, diabetes, BMI>30. Tacrolimus was identified as a protective factor for mortality. Conclusion(s): Liver transplant patients present additional risk factors of mortality related to immunosuppression. Immunosuppression's role in the progression to severe infection and mortality may correlate with different drugs. The present research suggests a safe use of Tacrolimus during the COVID-19 pandemic and highlights the need for further studies about post-transplant immunosuppression in patients at high risk of mortality.

BELZUTIFAN-INDUCED HYPERSENSITIVITY PNEUMONITIS

SESSION TITLE: Using Imaging for Diagnosis Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Immunotherapy is now a standard of care in solid-tumor oncology following the approvals of CTLA-4 and PD-1 inhibitors. Belzutifan, a small-molecule HIF-2a inhibitor, has recently gained FDA-approval for the treatment of advanced von Hippel-Lindau (VHL) associated renal cell carcinomas. CASE PRESENTATION: A 63-year-old female presented to our hospital with a one-day history of progressive dyspnea. Medical history is significant for metastatic renal cell carcinoma with pulmonary metastasis. Family and social history were noncontributory. Her cancer diagnosis was established in 2019 and had undergone cytoreductive nephrectomy and treatment with axitinib/pembrolizumab. As she had little improvement with immunotherapy, she was enrolled in a clinical trial at Memorial Sloan Kettering. Due to further disease progression, she was transitioned to lenvatinib/everolimus, though the treatment was discontinued due to anorexia and worsening pulmonary symptoms. Further work up revealed that she had ERG, MPL, VHL gene mutations. Thus, she was started on belzutifan two weeks prior to her presentation. Initial vitals were significant for hypoxia on room air that recovered with high flow nasal cannula (40L/80%). Physical examination was remarkable for severe respiratory distress with coarse breath sounds bilaterally. Laboratory studies revealed an acute leukocytosis with a neutrophilic prominence and a chronic metabolic alkalosis. COVID, flu PCR were negative. Chest x-ray demonstrated diffuse bilateral reticulonodular opacities. CTA revealed innumerable pulmonary nodules with areas of mass-like consolidation and a loculated left-sided pleural effusion. She was covered with azithromycin/ceftriaxone along with high-dose steroids and was admitted to the stepdown unit for further management. While in stepdown, she had a left PleurX catheter placed given her large effusion which was complicated by bloody output that required one unit of blood. Despite high-dose steroids, she had persistent hypoxia. As she remained unstable, goals of care discussions were held, which ultimately led to a change in code status to comfort measures. All aggressive measures were discontinued. She was started on comfort medications and ultimately passed away. DISCUSSION: Currently, neoplasms associated with VHL mutations are managed surgically to minimize the risk of metastatic disease. Nearly 70% of all patients with VHL mutations will develop renal cell carcinomas which means most patients undergo numerous surgical procedures. HIF-2a inhibition therefore offers an effective alternative that could reduce surgical burden and offer a new approach to management of VHL-associated disease. However due to its new approval, several adverse effects have yet to be documented. CONCLUSIONS: We report the only known case of Belzutifan-induced hypersensitivity pneumonitis and hope this case will become a useful contribution to the literature. Reference #1: Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R;MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021 Nov 25;385(22):2036-2046. doi: 10.1056/NEJMoa2103425. PMID: 34818478. DISCLOSURES: No relevant relationships by Garrett Fiscus No relevant relationships by Niala Moallem No relevant relationships by Raj Parikh

Causes of unplanned hospitalizations and factors associated with in-hospital mortality among patients receiving chemotherapy treatment

Background: Hospitalizations during cancer treatment are common, can impact quality of life and the progress of the treatment. We aimed to investigate the main causes of hospitalizations and factors associated with in-hospital mortality for patients receiving chemotherapy. Methods: This retrospective study included patients (pts) with solid tumors, who received outpatient chemotherapy in the 30-day period before unplanned admission to a cancer center in Brazil, from February to December of 2021. Patients with COVID-19 diagnosis were excluded. We retrieved clinical and laboratory data from health records. Logistic regression univariable and multivariable models were performed to analyze the association of the variables and in-hospital mortality as dependent outcome. Results: 784 pts were included, median age at hospitalization was 60 (IQR 49-68), and 57% were female. Most patients had ECOG 0-1 (61%) and nearly 70% had metastatic disease at admission. The most common primary tumors were colorectal (21.6%), breast (20.1%), lung (8.6%), and gastric (8.6%). Over half (56%) received platin-based regimens, usually in association with fluoropyrimidines or taxanes. Pain (33%), nausea (23%) and fever (16%) were the most referred symptoms at admission. The main diagnosis at were infection (32%), followed by disease progression (DP) (29%), and chemotherapy associated toxicity (26%). A total of 174 (22%) pts required intensive care unit support during hospital stay. The in-hospital overall mortality rate was 18%. Univariable analysis revealed poor ECOG-PS, grade 3 anemia, grade 3 thrombocytopenia and DP associated with in-hospital mortality. In the final multivariable model, ECOG ≥ 2 (OR 1.99, CI 95% 1.33 - 2.99, p <0.001), DP (OR 4.62, CI 95% 3.07 - 7.00, p <0.001) and grade 3 anemia (OR 2.38, CI 95% 1.45 - 3.87, p<0.001) remained statistically associated with in-hospital mortality. Conclusions: A substantial percentage of unplanned admissions after chemotherapy treatment are due to toxicity. Poor performance status, progression of disease on admission and severe anemia are associated with worse in-hospital prognosis. Grade 3 anemia on admission was the only toxicity associated with in-hospital mortality. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: R.C. Bonadio: Personal, Expert Testimony: AstraZeneca, Ache;Personal, Research Grant: Novartis;Personal, Roche. All other authors have declared no conflicts of interest.

Predictors of in-hospital mortality after unplanned admissions among adults with cancer aged 80 years and older

Background: Patients older than 80 years with cancer are more likely to be late-diagnosed, and less likely to receive optimal cancer treatment, compared to younger geriatric patients. Understanding the factors that influence these patient's outcomes is essential to guide their management and proper choice of assistance. Methods: A retrospective cohort of patients with solid tumors older than 80 years admitted to a tertiary, publicly-funded, cancer center in Brazil, from February 1st to December 31st, 2021. COVID-19 diagnoses were excluded. We collected data on staging, body mass index (BMI), comorbidities, ECOG-PS, symptoms, admission diagnoses, and in-hospital mortality. The age-adjusted Charlson Comorbidity Index [CCI] was further calculated. We investigated the association between collected variables of interest and in-hospital mortality with uni and multivariable logistic regression models. Results: Of 440 patients, the median age was 84 (IQR 81-87) and 58% were men. Prevalent cancer diagnoses were prostate (22%), breast (12%), colon (9.5%), and lung cancer (8.1%). Before admission, 42% of patients had distant metastasis, while 21% had no evidence of disease. Two-thirds of patients had poorer ECOG-PS (≥2), and the median CCI was 10 (IQR 8-11). Comorbidities included cardiovascular disease (29%), chronic renal disease (13%), dementia (9.5%) and COPD (9.1%). Pain (27%), dyspnea (18%), and altered level of consciousness (16%) were the most prevalent complaints. During hospitalization, 35% had an infection diagnosis and 26% had progression of disease. The overall in-hospital mortality rate was 25%. Higher CCI (OR 1.24, 95%CI 1.11-1.38), poorer ECOG-PS (OR 2.17, 95%CI 1.29-3.77), and progression of disease (OR 2.77, 95%CI 1.62-4.75) were associated with in-hospital mortality after univariable regression and remained all statistically significant in the multivariable model. BMI and age were not associated with poorer outcomes. Conclusions: Hospitalized patients with cancer aged 80 years and older have a high mortality rate. The Charlson Comorbidity Index, a comorbidity burden score that includes cancer staging, correlates with in-hospital mortality and therefore could guide supportive care decisions for older adults. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: R.C. Bonadio: Financial Interests, Personal, Expert Testimony: AstraZeneca, Ache;Financial Interests, Personal, Research Grant: Novartis;Financial Interests, Personal, Sponsor/Funding: Roche. All other authors have declared no conflicts of interest.

Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): Primary analysis of a phase II study

Background: CSCC is highly immune-responsive;a prior pilot study demonstrated a high rate of pathologic complete response (pCR) or major pathologic response (MPR, ≤10% viable tumor), using cemiplimab anti-programmed death 1 (PD-1) therapy in the neoadjuvant setting. Here, we present the primary analysis of a confirmatory, open-label, multicenter, Phase 2, single-arm trial of neoadjuvant cemiplimab in pts with resectable Stage II–IV (M0) CSCC. Methods: Pts received cemiplimab 350 mg IV q3W for up to 4 doses before surgery. The primary endpoint was pCR rate per independent central pathologic review (ICPR). Key secondary endpoints included MPR rate per ICPR, objective response rate (ORR;complete response [CR] + partial response [PR]) per RECIST v1.1, investigator-assessed pCR and MPR, safety and tolerability. Results: At data cutoff date of 01 Dec 2021, 79 pts were enrolled (67 male;median age 73.0 yrs [range, 66.0–81.0];ECOG performance status 0 (n=60) and 1 (n=19) with stage II (n=5), III (n=38), or IV(M0) (n =36) disease;62 pts received all 4 doses (median number of doses given (Q1:Q3), 4 (4:4);70 pts underwent surgery. The study met its primary endpoint: pCR was observed in 40 (50.6%) pts (95% confidence interval [CI], 39.1–62.1%). MPR was observed in an additional 10 (12.7%) pts (95% CI, 6.2–22.0%). ORR was 68.4% (95% CI, 56.9–78.4) (5 CR, 49 PR, 16 stable disease, 8 progressive disease (PD), 1 non evaluable. Reasons 9 pts did not have surgery: 3 responders declined surgery, 2 lost to follow-up or noncompliance, 2 had inoperable PD, 2 due to AE. Fourteen (17.7%) pts experienced Grade ≥3 AE. Four pts died due to AEs: 1 exacerbation of cardiac failure, 2 myocardial infarctions, and 1 COVID-19 pneumonia. The most common AEs regardless of attribution (all grades) were fatigue (30.4%), rash maculo-papular (13.9%), diarrhea (13.9%) and nausea (13.9%). Conclusions: The pCR + MPR of 63.3% by ICPR in pts with Stage II–IV (M0) CSCC is the highest observed in a multicenter anti-PD-1 neoadjuvant monotherapy study for any solid tumor type. The safety profile of neoadjuvant cemiplimab is consistent with previous anti-PD-1 monotherapy experience. Ongoing follow-up will describe disease-free survival. Clinical trial identification: NCT04154943. Editorial acknowledgement: Medical writing support was provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Legal entity responsible for the study: Regeneron Pharmaceuticals, Inc., and Sanofi. Funding: Regeneron Pharmaceuticals, Inc., and Sanofi. Disclosure: N. Gross: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Board: PDS Biotechnology, Shattuck Labs and Genzyme;Financial Interests, Personal, Advisory Role: PDS Biotechnology, Shattuck Labs and Genzyme. D.M. Miller: Financial Interests, Personal, Advisory Role: Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron, Sanofi Genzyme;Financial Interests, Personal, Ownership Interest: Checkpoint Therapeutics;Financial Interests, Personal, Research Grant: Kartos Therapeutics, NeoImmune Tech, Inc., Regeneron Pharmaceuticals, Inc. N. Khushanlani: Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Bristol Myers Squibb, HUYA Bioscience International, Merck, Novartis, GlaxoSmithKline, Celgene, Amgen;Financial Interests, Personal, Advisory Board: EMD Serono, Regeneron Pharmaceuticals, Inc., Genentech, AstraZeneca (data safety monitoring committee), Merck, Array Biopharma, Jounce Therapeutics, Immunocore, Bristol Myers Squibb, HUYA Bioscience International;Financial Interests, Personal, Other, honoraria: Sanofi;Financial Interests, Personal, Stocks/Shares: Bellicum Pharmaceuticals, Mazor Robotics, Amarin, Transenetrix. V. Divi: Financial Interests, Institutional, Research Grant: Genentech. E.S. Ruiz: Financial Interests, Personal, Advisory Board: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Int rests, Personal, Advisory Role, consulting fees: Genentech, Leo Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Sanofi;Financial Interests, Personal, Member of the Board of Directors: Checkpoint Therapeutics. E.J. Lipson: Financial Interests, Personal, Other, Advisory board and consulting fees: Bristol Myers-Squibb, Eisai, Genentech, Immunocore, Instil Bio, MacroGenics, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, OncoSec, Pfizer, Rain Therapeutics, Regeneron, Sanofi;Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck, Regeneron. F. Meier: Financial Interests, Personal, Other, Travel support, speaker’s fees or advisor’s honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche and Sanofi;Financial Interests, Personal, Research Grant: Novartis and Roche. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma, Pfizer;Financial Interests, Personal, Advisory Board: Prelude Therapeutics, Elevar Therapeutics, Regeneron Pharmaceuticals. J.L. Atlas: Financial Interests, Personal, Advisory Role: Regeneron Pharmaceuticals, Inc., Sanofi, and Bristol Myers Squibb. J.L. Geiger: Financial Interests, Institutional, Research Grant: Alkermes, Debio, Merck, Regeneron Pharmaceuticals, Inc., and Roche/Genentech;Financial Interests, Personal, Advisory Role: Exelixis, Merck and Regeneron Pharmaceuticals, Inc. A. Hauschild: Financial Interests, Personal and Institutional, Other, Institutional grants, speaker’s honoraria and consultancy fees: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Provectus and Roche;Financial Interests, Institutional, Other, Institutional grants and consultancy fees: EMD Serono, Philogen and Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Advisory Role: OncoSec Medical. J.H. Choe: Financial Interests, Personal, Advisory Role: Exelixis, Coherus Biosciences, Regeneron Pharmaceuticals, Inc. B.G.M. Hughes: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer and Roche;Financial Interests, Institutional, Research Grant: Amgen. S. Yoo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. K. Fenech: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. H. Han: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.G. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.;Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. D. Rischin: Financial Interests, Institutional, Research Grant: Regeneron Pharmaceuticals, Inc., Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Merck KGaA, Bristol Myers Squibb, GlaxoSmithKline, ALX Oncology;Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb;Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc., Sanofi, GlaxoSmithKline, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Synergistic anti-tumor effect of Allocetra-OTS in combination with immune checkpoint inhibitors (ICI)/chemotherapy/CAR T, through in-vivo reprogramming of macrophages

Background: ICI revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Here we investigated the anti-tumoral effect of Allocetra—OTS cellular therapy, in solid tumor models. Methods: Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis.Balb/c mice were inoculated in the peritoneal cavity with AB12 (mesothelioma) stably transduced with pLenti-PGK-V5-Luc-Neo for IVIS visualization and treated with anti-CTLA4, anti-PD1, or cisplatin, with or without Allocetra-OTS (also administered as monotherapy). Kaplan-Meier log rank test was done for survival. CAR T model was induced in SCID-Bg mice were inoculated intraperitoneally with human HeLa-CD19, followed by treatment with 10×109 cells of Allocetra-OTS or vehicle, and 1×107 CD19-CAR T cells or mock T cells. Results: Anti-CTLA4 therapy significantly improved survival from mean 34±9 to 44.9 ±20 days (p<0.05). However, Allocetra-OTS monotherapy improved survival to 52.3 ±20 days (p<0.02) and anti-CTLA4 + Allocetra-OTS combination therapy to 86.7±20 days (p<0.0001) with complete cancer remission in 60-100% of mice. Similar results were seen in combination therapy with either anti-PD1 or cisplatin. In the CAR-T model, SCID-Bg mice survived 30±5 days (range 27–37) and were sacrificed or died from tumor progression. Results were verified using IVIS of intraperitoneal HeLaCD19-Luc cells. CAR T cell therapy significantly improved survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further improved survival to 75±10 (p < 0.001) with 20-40% complete remission. Conclusions: During intraperitoneal tumor progression, Allocetra-OTS as monotherapy or in combination with ICI, cisplatin or CAR-T therapy, significantly reduced tumor size and resulted in complete remission in up to100% treated mice. Based on excellent safety profile in > 40 patients treated in prior clinical trials for sepsis and COVID-19, phase I/II clinical trial of Allocetra-OTS plus chemotherapy is planned for Q3 2022, and a second phase I/II clinical trial of Allocetra-OTS plus anti-PD1, as a second- and third-line therapy in various cancers, is planned for Q4 2022. Legal entity responsible for the study: The authors. Funding: Enlivex Therapeutics Ltd. Disclosure: D. Mevorach: Financial Interests, Personal, Royalties, Founder & CSO: Enlivex Therapeutics LTD. E. Yalon, E. Regev, C. Ankri, O. Hershkovitz, Y. Shabat, B. Reicher: Financial Interests, Personal, Full or part-time Employment: Enlivex Therapeutics LTD.

Assessing the accuracy of multiple prognostic scores for immune checkpoint inhibitors (ICI) in patients with advanced solid tumors

Background: Many patients fail to achieve a clinical benefit from ICI. Several scores have been developed to improve ICI candidates selection but it is uncertain which one better predicts patients’ outcome. Here, we performed a direct comparison of the most successful scores. Methods: This is a sub-analysis of the immunoblood prospective observational study that enrolled patients diagnosed with advanced solid tumors treated with ICI. Main clinicopathological data were retrieved from medical records and responses assessed according to RECIST 1.1 criteria. LIPI, RMH, PMH, dNLR, NLR, PIPO and GRIm scores were calculated. Receiving operator characteristics (ROC) curves and their area under curve (AUC) were used to predict PFS and durable clinical benefit (DCB;stable disease≥6 months or better). Associations with PFS, OS and DCB, where assessed with Cox and logistic regressions. Scores’ correlation was assessed with Spearman rho. Significance was set at p<0.05. Results: We recruited 155 patients (65% male, mean age 63). NSCLC (28%), colorectal (20%) breast (9%) H&N (6%) cancer and melanoma (6%) were the most frequent tumor types. Frequency of the high risk/bad outcome group of each score were: LIPI 13%, RMH 36%, PMH 54%, GRIm 14%, PIPO 6%, NLR 32% and dNRL 27%. Fair accuracy in identifying patients at higher risk of progression or mild accuracy in predicting DCB were observed for the RMH (AUC PFS: 0.7, 95%CI: 0.6-0.8;AUC DCB: 0.6, 0.5-0.8) and LIPI (AUC PFS: 0.7, 95%CI: 0.6-0.8;AUC: 0.6, 0.5-0.7) scores. All other scores provided poor/no accuracy. No significant difference was observed between RMH and LIPI AUC for PFS and DCB (both p>0.05). Additionally, only LIPI and RMH were associated with PFS (p=0.001;p<0.001), OS (p<0.001;p=0.001) and DCB (p=0.034;p=0.010) at univariate analyses. At multivariate analyses RMH and LIPI remained significantly associated with PFS (p=0.030;p=0.021) and OS (p=0.012;p<0.001). A strong correlation between both scores (rho=0.72, p<0.001) was observed. Conclusions: RMH and LIPI scores were sufficiently reliable in assessing the prognosis of patients with advanced solid tumors treated with ICI. They were superior to other analyzed scores in our population and highly correlated. Legal entity responsible for the study: Hospital Clinic y Provincial de Barcelona, Medical Oncology Department. Funding: Has not received any funding. Disclosure: J. Garcia-Corbacho: Financial Interests, Personal, Advisory Board, FGFR inhibitors implementation in clinical practice: Johnson & Johnson Pharmaceutical;Financial Interests, Institutional, Invited Speaker, Participation in clinical trials of the company as PI: Johnson and Johnson Pharmaceutical, Boehringer Ingelheim, Astellas, Cytomx, Incyte, Lilly, Menarini, Merck, Bayer, AstraZeneca, Amgen, Daiichi Sankyo. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. N. Baste Rotllan: Non-Financial Interests, Advisory Role: Eisai, MSD, Merck Serono, BioNTech, Roche, BMS, Exelixis. A. Prat: Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo;Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc;Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo;Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia Inno. Research;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.;Financial I terests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech;Financial Interests, Personal, Royalties: Reveal Genomics;Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis;Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo;Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

A multi-centre national study of COVID-19 infection in cancer patients

Background & aims: COVID19 disproportionately affects the immunosuppressed, but its epidemiology over time is incompletely characterised. We describe Australian experiences of COVID19 in a national observational study of patients with malignancy. Methods: An ongoing multisite prospective cohort study of adult COVID19 patients with active cancer was conducted. Clinical and laboratory data over 28 months (1/3/20-22/7/22) was collated from 15 hospitals. Results: There were 491 patients included. Patients were a median of 63(IQR:50-71) years with majority male (254,52%). Solid organ malignancy was most common (296,60%), followed by haematological malignancy (180,37%), then both (15,4%). Most common solid tumour was breast cancer (74/296,25%);most common haematological cancer was lymphoma (102/180,57%). Majority (275,56%) were undergoing cancer treatment at COVID19 diagnosis. From 2020-2022, patients presented less with lower respiratory tract infections (57%,36%,5%) with increasing outpatient management (26%,50%,67%). Improved mortality was seen (27%,19%,11%). Median inpatient length of stay was 8(4-11) days. Intensive care admission was low (21,4%). For patients who had repeated respiratory PCR testing, median time from first to last positive test was 17(7-25, n = 123) days. Cancer treatment modification occurred in 18(4%) and delay in 74(15%). Conclusion: Despite improvements in outcomes, COVID19 still results in morbidity with impacts on cancer treatment. This preliminary data shows that cancer patients remain a vulnerable group and should be prioritised for public health interventions.