CD33 Expression on Peripheral Blood Monocytes Predicts Efficacy of Anti-PD-1 Immunotherapy Against Non-Small Cell Lung Cancer

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related deaths globally. Immune checkpoint blockade (ICB) has transformed cancer medicine, with anti-programmed cell death protein 1 (anti-PD-1) therapy now well-utilized for treating NSCLC. Still, not all patients with NSCLC respond positively to anti-PD-1 therapy, and some patients acquire resistance to treatment. There remains an urgent need to find markers predictive of anti-PD-1 responsiveness. To this end, we performed mass cytometry on peripheral blood mononuclear cells from 26 patients with NSCLC during anti-PD-1 treatment. Patients who responded to anti-PD-1 ICB displayed significantly higher levels of antigen-presenting myeloid cells, including CD9+ nonclassical monocytes, and CD33hi classical monocytes. Using matched pre-post treatment samples, we found that the baseline pre-treatment frequencies of CD33hi monocytes predicted patient responsiveness to anti-PD-1 therapy. Moreover, some of these classical and nonclassical monocyte subsets were associated with reduced immunosuppression by T regulatory (CD4+FOXP3+CD25+) cells in the same patients. Our use of machine learning corroborated the association of specific monocyte markers with responsiveness to ICB. Our work provides a high-dimensional profile of monocytes in NSCLC and links CD33 expression on monocytes with anti-PD-1 effectiveness in patients with NSCLC

Caracterización de los eventos inmunológicos diferenciales en pacientes con cáncer de pulmón de célula pequeña tratados con quimioterapia con o sin ipilimumab

[spa] El cáncer de pulmón de célula pequeña (CPCP) es el subtipo mas agresivo del cáncer de pulmón. Mas de la mitad de los pacientes se diagnostican con enfermedad diseminada, donde el tratamiento de elección desde la década de 1980 ha sido la quimioterapia basada en platino. A pesar de que tras el tratamiento se consiguen respuestas espectaculares, la progresión de la enfermedad ocurre de manera precoz y generalmente la enfermedad se vuelve resistente a todos los tratamientos disponibles. En este contexto, el pronóstico del CPCP es infausto, con una supervivencia mediana que raramente excede el año de vida. El CPCP se caracteriza por la presencia de una autoinmunidad contra el tumor, reflejada por la elevada incidencia de los síndromes paraneoplásicos. Este hecho, acompañado de la alta carga mutacional evidenciada en CPCP, sugieren que la inmunoterapia es una estrategia prometedora en esta enfermedad. Los anticuerpos anti-CTLA-4 y anti-PD-1/L1 han demostrado tener actividad en CPCP y obtener respuestas duraderas. De hecho, un fármaco anti-PD1 ha sido aprobado recientemente en primera línea de tratamiento en combinación con quimioterapia. El objetivo de este proyecto fue identificar los eventos inmunológicos diferenciales observados en pacientes tratados con quimioterapia + ipilimumab (anti-CTLA-4) en comparación con aquellos tratados con quimioterapia sola, y dentro de los pacientes tratados con quimioterapia + ipilimumab, hallar las diferencias entre los pacientes con largas supervivencias. Para llevar a cabo esta evaluación, contamos con la disponibilidad de muestras seriadas de pacientes con CPCP tratados con quimioterapia + ipilimumab y treatados con quimioterapia sola, en diferentes puntos del tratamiento. Hemos analizado el perfil de autoanticuerpos y citoquinas en suero, y hemos caracterizado mediante citometría de flujo las subpoblaciones linfocitarias periféricas. Nuestros hallazgos indican que los autoanticuerpos no sufren variaciones en su concentración como consecuencia directa del ipilimumab a lo largo del tratamiento. Por el contrario, el bloqueo de CTLA-4 sí que modula de manera significativa tanto los niveles de citoquinas como la proporción de las diferentes subpoblaciones linfocitarias. Hemos sido capaces de comprobar el rol pronóstico que ejercen los autoanticuerpos en CPCP, así como el papel predictivo de determinadas citoquinas en suero. Por último, hemos detectado que existen algunos patrones de subpoblaciones de células T y NK periféricas que se relacionan con supervivencia y toxicidad asociada al tratamiento con ipilimumab en CPCP.[eng] Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. More than half of patients are diagnosed at extensive stage, where platinum-based chemotherapy has been the systemic standard treatment since the mid ‘80s. Although robust and often dramatic clinical responses are achieved after first-line treatment, disease progression takes place soon and it is usually resistant to available treatments. In this scenario, outcomes remain poor, with a median overall survival that rarely exceeds one year. SCLC is characterized by the presence of autoinmmunity, reflected by the incidence of autoimmune paraneoplastic syndromes. This fact, as well as the high tumor mutational burden found in this disease suggest that immune modulation is a promising strategy in SCLC. Anti-CTLA-4 antibodies and anti-PD-1/L1 antibodies have showed activity and durable responses. In fact, an anti-PD-L1 has been recently approved in first line treatment in addition to standard chemotherapy. The aim of this project was to identify the differential immunological events observed in patients treated with chemotherapy and ipilimumab (anti-CTLA-4 antibody) vs. those in patients treated with standard chemotherapy, and in those patients treated with ipilimumab with long survival vs. those with short survival. To this end we had availability of serial samples from patients treated with ipilimumab + chemotherapy and chemotherapy alone over time. We assessed cytokine and autoantibody profiles in serum samples, and peripheral lymphocyte populations by flow cytometry. We found that unlike autoantibodies, serum cytokines and specific lymphocyte peripheral subpopulations were modulated after CTLA-4 blockade. We were able to verify the prognostic role of autoantibodies, and to ascertain the predictive role of cytokines. Lastly, we detected particular patterns of peripheral T and NK cells populations linked to survival and toxicity in SCLC. With this project we were able to depict a comprehensive scene of the relevant immunological events in SCLC, which will lead us to a better selection of patients who could benefit from immunotherapy and thus to design appropriate clinical trials

MET Inhibitors in Small Cell Lung Cancer: From the Bench to the Bedside

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The different systemic treatment approaches attempted in the last 35 years have not improved overall survival in the advanced stage. Targeted therapies assessed in clinical trials have failed to show efficacy against SCLC. Within the potentially interesting targets, the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway activation is associated with worse survival and chemoresistance in SCLC. Preclinical data suggest that the inhibition of the MET pathway can revert chemoresistance and prevent tumor growth. Recently, immunotherapy has shown modest but relevant activity in SCLC. Interestingly, MET modulation seems to be involved in increasing the efficacy of standard checkpoint inhibitors. Here, we review the preclinical and clinical data of MET inhibition in SCLC, and the role of this pathway in the immune response

Comprehensive NGS profiling to enable detection of ALK gene rearrangements and MET amplifications in non-small cell lung cancer

Introduction: Next-generation sequencing (NGS) is currently widely used for biomarker studies and molecular profiling to identify concurrent alterations that can lead to the better characterization of a tumor's molecular landscape. However, further evaluation of technical aspects related to the detection of gene rearrangements and copy number alterations is warranted. Methods: There were 12 ALK rearrangement-positive tumor specimens from patients with non-small cell lung cancer (NSCLC) previously detected via fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and an RNA-based NGS assay, and 26 MET high gene copy number (GCN) cases detected by FISH, selected for this retrospective study. All 38 pre-characterized cases were reassessed utilizing the PGDx™ elio™ tissue complete assay, a 505 gene targeted NGS panel, to evaluate concordance with these conventional diagnostic techniques. Results: The detection of ALK rearrangements using the DNA-based NGS assay demonstrated excellent sensitivity with the added benefit of characterizing gene fusion partners and genomic breakpoints. MET copy number alterations were also detected; however, some discordances were observed likely attributed to differences in algorithm, reporting thresholds and gene copy number state. TMB was also assessed by the assay and correlated to the presence of NSCLC driver alterations and was found to be significantly lower in cases with NGS-confirmed canonical driver mutations compared with those without (p=0.0019). Discussion: Overall, this study validates NGS as an accurate approach for detecting structural variants while also highlighting the need for further optimization to enable harmonization across methodologies for amplifications

Real-world data on T-DM1 efficacy - results of a single-center retrospective study of HER2-positive breast cancer patients

T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice

Comparison of different methods for defining hyperprogressive disease in NSCLC

Introduction: Hyperprogressive disease (HPD) as a consequence of immune checkpoint inhibitors in NSCLC has been reported in multiple studies. However, inconsistent results in incidence and survival outcomes within studies, together with different assessment methods, have led to increasing controversy regarding the concept of HPD. Methods: Consecutive patients treated with nivolumab (N = 42) or docetaxel (N = 37) were evaluated. HPD was quantified by applying three different methods (tumor growth rate [TGR], tumor growth kinetics [TGK], and Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]). HPD rates were compared between and within both cohorts using the different methods. Results: Using TGR, TGK, and RECIST 1.1, we identified seven (16.7%), seven (16.7%), and six (14.3%) patients with HPD in the nivolumab cohort and three (8.1%), four (10.8%), and five (13.6%) in the docetaxel cohort, respectively. We observed a higher concordance between TGR and TGK (90.1%) compared with RECIST 1.1 (31.3% and 37.5% with TGR and TGK, respectively). We found no significant differences in the overall survival between patients with progressive disease and HPD in either cohort. Conclusions: TGR and TGK revealed high concordance rates for identifying patients with HPD in NSCLC. The incidence of HPD was numerically higher in patients treated with immune checkpoint inhibitors. Standardization of methods for measuring HPD and its exploration in larger studies are needed to establish its clinical meaning in NSCLC

MultiCOVID: a multi modal deep learning approach for COVID-19 diagnosis

Abstract The rapid spread of the severe acute respiratory syndrome coronavirus 2 led to a global overextension of healthcare. Both Chest X-rays (CXR) and blood test have been demonstrated to have predictive value on Coronavirus Disease 2019 (COVID-19) diagnosis on different prevalence scenarios. With the objective of improving and accelerating the diagnosis of COVID-19, a multi modal prediction algorithm (MultiCOVID) based on CXR and blood test was developed, to discriminate between COVID-19, Heart Failure and Non-COVID Pneumonia and healthy (Control) patients. This retrospective single-center study includes CXR and blood test obtained between January 2017 and May 2020. Multi modal prediction models were generated using opensource DL algorithms. Performance of the MultiCOVID algorithm was compared with interpretations from five experienced thoracic radiologists on 300 random test images using the McNemar–Bowker test. A total of 8578 samples from 6123 patients (mean age 66 ± 18 years of standard deviation, 3523 men) were evaluated across datasets. For the entire test set, the overall accuracy of MultiCOVID was 84%, with a mean AUC of 0.92 (0.89–0.94). For 300 random test images, overall accuracy of MultiCOVID was significantly higher (69.6%) compared with individual radiologists (range, 43.7–58.7%) and the consensus of all five radiologists (59.3%, P < .001). Overall, we have developed a multimodal deep learning algorithm, MultiCOVID, that discriminates among COVID-19, heart failure, non-COVID pneumonia and healthy patients using both CXR and blood test with a significantly better performance than experienced thoracic radiologists

Evaluation of the host immune response assay SeptiCyte RAPID for potential triage of COVID-19 patients

Abstract Tools for the evaluation of COVID-19 severity would help clinicians with triage decisions, especially the decision whether to admit to ICU. The aim of this study was to evaluate SeptiCyte RAPID, a host immune response assay (Immunexpress, Seattle USA) as a triaging tool for COVID-19 patients requiring hospitalization and potentially ICU care. SeptiCyte RAPID employs a host gene expression signature consisting of the ratio of expression levels of two immune related mRNAs, PLA2G7 and PLAC8, measured from whole blood samples. Blood samples from 146 adult SARS-CoV-2 (+) patients were collected within 48 h of hospital admission in PAXgene blood RNA tubes at Hospital del Mar, Barcelona, Spain, between July 28th and December 1st, 2020. Data on demographics, vital signs, clinical chemistry parameters, radiology, interventions, and SeptiCyte RAPID were collected and analyzed with bioinformatics methods. The performance of SeptiCyte RAPID for COVID-19 severity assessment and ICU admission was evaluated, relative to the comparator of retrospective clinical assessment by the Hospital del Mar clinical care team. In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity: critical vs. mild (AUC = 0.93, p < 0.0001), critical vs. moderate (AUC = 0.77, p = 0.002), severe vs. mild (AUC = 0.85, p = 0.0003), severe vs. moderate (AUC = 0.63, p = 0.05). This discrimination was significantly better (by AUC or p-value) than could be achieved by CRP, lactate, creatine, IL-6, or D-dimer. Some of the critical or severe cases had “early” blood draws (before ICU admission; n = 33). For these cases, when compared to moderate and mild cases not in ICU (n = 37), SeptiCyte RAPID had AUC = 0.78 (p = 0.00012). In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity as defined by the WHO COVID-19 Clinical Management Living Guidance of January 25th, 2021. Measurements taken early (before a patient is considered for ICU admission) suggest that high SeptiScores could aid in predicting the need for later ICU admission