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Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these 'responsive' tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near-complete absence of lymphocytes from the tumor, so-called immunologically cold tumors. Here, we propose two broad approaches to convert 'cold' tumors into 'hot' tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor-beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen-presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

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BACKGROUND: KRAS mutations are found in 20-30 % of non-small cell lung cancers (NSCLC) and were traditionally considered undruggable. KRASG12C mutation confers sensitivity to KRASG12C covalent inhibitors, however its prognostic impact remains unclear. This study assesses the frequency, clinical features, prevalence of brain metastases and outcomes in KRASG12C NSCLC in a real-world setting. METHODS: Patients enrolled in the prospective Thoracic Malignancies Cohort (TMC) between July 2012 to October 2019 with recurrent/metastatic non-squamous NSCLC, available KRAS results, and without EGFR/ALK/ROS1 gene aberrations, were selected. Data was extracted from TMC and patient records. Clinicopathologic features, treatment and overall survival (OS) was compared for KRAS wildtype (KRASWT) and KRAS mutated (KRASmut); and KRASG12C and other (KRASother) mutations. RESULTS: Of 1386 NSCLC patients, 1040 were excluded: non-metastatic/recurrent (526); unknown KRAS status (356); ALK/EGFR/ROS1 positive (154); duplicate (4). Of 346 patients analysed, 144 (42 %) were KRASmut, of whom 65 (45 %) were KRASG12C. All patients with KRASG12C were active or ex-smokers, compared to 92 % of KRASother and 83 % of KRASWT. The prevalence of brain metastases during follow-up was similar between KRASmut and KRASWT (33 % vs 40 %, p = 0.17), and KRASG12C and KRASother (40 % vs 41 %, p = 0.74). The proportion of patients receiving one or multiple lines of systemic therapy was comparable. OS was similar between KRASmut and KRASWT (p = 0.54), and KRASG12C and KRASother (p = 0.39). CONCLUSION: Patients with KRASmut and KRASWT, and KRASG12C and KRASother NSCLC have comparable clinical features, treatment and survival. While not prognostic, KRASG12C may be an important predictive biomarker as promising KRASG12C covalent inhibitors continue to be developed.

PURPOSE: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. PATIENTS AND METHODS: Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research. RESULTS: From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL-based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. CONCLUSIONS: Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and co

Item does not contain fulltext, Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.

Introduction & Objectives: Nivo (anti-PD-1)has shown durable responses and manageable safety (ORR, 19.6%; grade 3-4 treatment-related AEs [TRAEs], 18%)in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN)production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti-PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD), oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)-naive advBC cohort are reported. Material(s) and Method(s): Dose-escalation methods in this phase 1/2a study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Result(s): As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had >=2 prior regimens. TRAEs occurred in 57% of pts (grade 3-4, 12%), the most common being fatigue (15%)and nausea (12%); 19 pts (4%)discontinued (DC)due to TRAEs and 3 pts (<1%)died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and in the advBC cohort (n=30), the frequency and severity of TRAEs and rate of DC due to TRAEs were lower with BMS-986205 100 vs 200 mg. Among the 27 pts with I-O-naive advBC, the ORR was 37% (3 CRs, 7 PRs)and the DCR was 56%, with a median duration of follow-up of 24 wk. Responses were deep and durable, with some lasting beyond DC; median duration of response was not reached (range, 16.1-51.7+ wk). ORR and DCR in select l-O-naive advBC pt subgr

Background AK104 is a tetrameric PD-1/CTLA-4 bispecific antibody, based on the Akeso Tetrabody platform [1]. A number of studies have shown that combined PD-1 and CTLA-4 blockade is associated with a higher response rate in multiple tumor types. Toxicity associated with anti- CTLA-4 agents in particular is dose limiting, thereby limiting full potential for PD-1 and CTLA-4 combination therapy. AK104 introduces novel T cell targeting mechanisms of action that may provide an improved therapeutic index and a favorable toxicity profile compared to PD-1 and CTLA-4 combination therapy. Methods A multicenter, Phase I, open-label dose escalation and expansion study in solid tumors (NCT03261011) began in Oct 2017, evaluating the safety, efficacy and recommended phase 2 dose of AK104 administered IV every 2 weeks (q2w). For dose escalation, pts were enrolled at dose cohorts of 0.2, 0.5, 1.0, 2.0, 4.0, 6.0 and 10.0 mg/kg. Pharmacodynamic studies examined Ki67 expression on peripheral T-cells and receptor occupancy (RO). Results As of 8 July 2019, 40 pts, median age 66.5 years [31-85], have received AK104 at doses of 0.2 mg/kg (n = 1), 0.5 mg/kg (n = 3), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 3), 4.0 mg/kg (n = 3), 6.0 mg/kg (n = 21) and 10.0 mg/kg q2w (n = 3). Median number of doses was 4 (1- 26). Treatment-related adverse events (TRAEs) occurred in 62.5% of pts. G3 TRAEs occurred in 10% [4/40], there were no G4 TRAEs. TRAEs leading to treatment discontinuation occurred in 7.5% [3/40]). Most frequent TRAEs were rash (23%), infusion reaction (15%), fatigue (15%), nausea (13%), and pruritus (10%)(Figure 1). Of 21 evaluable pts treated at doses >= 2 mg/kg, ORR was 28.6% (6/21) and disease control rate (DCR) was 47.6% (10/21) (Figure 2). Six responders remain on treatment (Gastric cancer, TNBC, mesothelioma, and largecell neuroendocrine carcinoma each and 2 MSI-H CRC). Peripheral CD4+ T-cells demonstrated dose dependent increases in Ki-67 expression at D8. Conclusions AK104 can be given

Background: Programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), play critical roles in the immune modulation of tumor progression. Tislelizumab is a humanized IgG4 monoclonal antibody against PD-1. A first-inhuman, phase 1A/1B study (NCT02407990) demonstrated that single-agent tislelizumab was generally well tolerated and showed evidence of antitumor activity in patients with advanced solid tumors at the recommended dose of 200 mg administered every 3 weeks (Q3W). BGB-A333 is a humanized IgG1 monoclonal antibody against PD-L1 which increased functional activities of human T cells in in vitro studies, and showed antitumor activity in various cancer xenograft models. BGB-A333 blocks the interaction between PD-L1 and CD80 (B7-1), which in turn release the inhibitory signals to Tcells, enhances T-cell expansion, and prevents T-cell energy induction. Therefore, a combination of anti-PD-1 and anti-PD-L1 can potentially elicit stronger antitumor immunity through blockade of multiple complementary immune-suppressive signals in tumor microenvironments. Method(s): This open-label study (NCT03379259) consists of two phases, each phase consisting of two parts. Phase 1 is designed to investigate the safety and tolerability of the BGB-A333 RP2D alone and in combination with tislelizumab. Phase 1A (BGB-A333 dose escalation) will follow a 3+3 design to establish the RP2D of BGB-A333. Phase 1B (combination dose confirmation) explores safety and tolerability of IV BGB-A333 (determined from dose escalation) in combination with IV tislelizumab (200 mg Q3W). Phase 2 is designed to evaluate the antitumor activity of BGB-A333 alone and in combination with tislelizumab. Phase 2A (BGB-A333 dose expansion) will enroll patients into two cohorts: non-small cell lung cancer and urothelial carcinoma. Phase 2B (combination dose expansion) will enroll patients with specific tumor types, which will be chosen based on data from phase 2A and other studies. The primary en

Background: Nivo (antiPD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3-4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti-PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)naive advBC cohort are reported. Method(s): Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1. 1 (includes unconfirmed responses). Result(s): As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had >=2 prior regimens. TRAEs occurred in 57% of pts (grade 3-4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-Onaive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 >1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusion(s): BMS-986205 + nivo was well tolerated in hea

Background Tislelizumab (BGB-A317), an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcgammaR on macrophages in order to abrogate antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. Previous reports from early phase studies suggest tislelizumab was generally well tolerated and had antitumor activity in patients (pts) with advanced solid tumors. Clinical effects of tislelizumab LTE (>12 mo) in pts enrolled in the first-in-human study (NCT02407990) are presented here. Methods Patients with advanced solid tumors received IV tislelizumab 0.5, 2, 5, or 10 mg/kg Q2W, 2 or 5 mg/kg administered Q2W or Q3W, or 200 mg IV Q3W. Antitumor activity was assessed by RECIST v1.1 criteria; PD-L1 expression was retrospectively assessed with the VENTANA PD-L1 (SP263) assay. Results As of 31 Aug 2018, 63 of the 451 pts received tislelizumab for >12 mo. In these 63 pts, median age was 64 yr and 70% had received >=1 prior systemic therapy. Tislelizumab LTE was most common in NSCLC (n=9), HCC (n=7), and bladder and ovarian (n=5 each) cancers. Four of the 5 pts who achieved CR during this study had LTE to tislelizumab (Table); all 4 pts were PD-L1+ (>=1% expression on tumor cells). Across the LTE cohort, ORR was 66.7%; PR and SD were observed in both PD-L1+ and PD-L1- tumors. The median time to CR/PR (3.7 mo) and duration of CR/PR (21.1 mo) were longer in pts with LTE than pts who responded but did not remain on treatment for >12 mo (2.1 and 6.3 mo, respectively). Rash was the only treatment-related AE (TRAE) reported in >=15% of pts. Most TRAEs were of mild or moderate severity; arthritis, diarrhea, fatigue, granuloma, hyperglycemia, and lichenoid keratosis (n=1 each) were the only grade >=3 TRAEs reported with tislelizumab LTE. Conclusion Tislelizumab remained well tolerated for >12 mo and elicited durable responses in pts with a variety of tumor types regardless of PD-L1 status

Background: Tislelizumab, a humanized IgG4 monoclonal Ab with high affinity and specificity forPD-1, was engineered to minimize binding to FcgammaRonmacrophages, thus abrogating antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports fromthis first-in-human study (NCT02407990), and other early phase studies, suggested tislelizumab was generally well tolerated and had antitumor activity in pts with advanced solid tumors.Here we report the effects of tislelizumab in a subset of pts enrolled in phase 1A/1B. Method(s): Eligible patients with advanced esophageal [EC], gastric [GC], hepatocellular [HCC], and non-small cell lung [NSCLC] cancers were treated with tislelizumab 2 or 5 mg/kg every 2 wks or 3 wks (Q3W); 97% received 5mg/kg Q3W. Adverse events (AEs) were assessed per NCI-CTCAE 4.03 criteria and tumor assessments performed every 9 wks using RECIST v1.1. Result(s): Of the 207 pts (EC=54; GC=54; HCC=50; NSCLC=49), 114 were male 111 were Asian, 78 were Caucasian and all but one received>=1 prior anticancer therapy. Treatment-related AEs (TRAEs) occurring in >=5% of pts were fatigue (8.7%) decreased appetite (6.8%), rash (6.8%), hypothyroidism(6.3%), and nausea (6.3%). Grade >=3 TRAEs occurring in >=2 pts were pneumonitis (n=3), elevated AST (n=3) and elevated ALT (n=2). Grade 5 TRAEs occurred in two pts: pneumonitis in a pt with NSCLC with compromised pulmonary function and acute hepatitis in a pt with HCC with rapidly progressing disease. As of 27 Apr 2018, a total of 23 pts remained on study treatment; median duration of study follow-up ranged from 4.9-9.9 mo. Responses in each tumor type are presented in the table. (Table Presented) Conclusion(s): Tislelizumab was generally well tolerated and antitumor activity was observed in each tumor type. Tislelizumab, as monotherapy and in combination, is being evaluated in multiple phase 2 and phase 3 studies.

Background: NIVO (anti-PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3-4 treatment-related AEs [TRAEs], 18%) in pts with advBC (Sharma P, et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates development of regulatory T cells and suppresses effector T-cell proliferation. Anti-PD-1 therapy can upregulate IDO1, supporting the rationale for combining NIVO with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD), oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS- 986205 + NIVO demonstrated a favorable safety profile and antitumor activity in heavily pretreated pts with select solid tumors (Luke J, et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the advBC cohort are reported. Method(s): Dose-escalation methods of this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + NIVO 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed [u] responses). Prior IO therapy was permitted in the advBC cohort. Result(s): As of Dec 15, 2017, 434 pts received BMS-986205 + NIVO. TRAEs were reported in 51% of pts (grade 3-4, 12%), the most common being fatigue (13%) and nausea (10%); 16 pts (4%) discontinued due to TRAEs, and 1 pt died due to a TRAE (myocarditis). With a median follow-up of 17 wk (range, 4-53), the ORR among 29 pts with advBC was 34% (1 u CR, 9 PRs [1 u]), and the disease control rate (DCR) was 48%. Of 29 pts, 26 had no prior IO therapy; ORR in these pts was 38% (1 u CR, 9 PR [1 u]), and the DCR was 54%. ORR in pts with tumor PD-L1 >= 1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 15) vs < 1% (n = 11) was 47% vs 27%. Conclusion(s): BMS-986205 + NIVO was well tolerated, with a safety profile similar to that o

Background: Immuno-oncology (IO) is rapidly evolving in early drug development. We aimed to develop and prospectively validate a prognostic index for patients treated in IO phase I trials to assist with patient selection. Methods: The development cohort included 192 advanced solid tumor patients treated in 13 IO phase I trials, targeting immune checkpoint and/or co-stimulatory molecules. A prognostic scoring system was developed from multivariate survival analysis of 10 clinical factors, and subsequently validated in two independent validation cohorts (n = 152 and n = 80). Results: In the development cohort, median age was 57.5 years (range = 20.4-84.8 years). Median progression-free survival and overall survival (OS) were 13.4 and 73.6 weeks, respectively, 90-day mortality was 16%, and overall response rate was 20%. In multivariate analysis, Eastern Cooperative Oncology Group performance status greater than or equal to 1 (hazard ratio [HR] = 3.2, 95% confidence interval [CI] = 1.8 to 5.7; P < .001), number of metastatic sites greater than 2 (HR = 2.0, 95% CI = 1.3 to 3.1; P = .003), and albumin less than the lower limit of normal (HR = 1.8, 95% CI = 1.2 to 2.7; P = .007) were independent prognostic factors; comprising the Princess Margaret Immuno-oncology Prognostic Index (PM-IPI). Patients with a score of 2-3 compared with patients with a score of 0-1 had shorter OS (HR = 3.4, 95% CI = 1.9 to 6.1; P < .001), progression-free survival (HR = 2.3, 95% CI = 1.7 to 3.2; P < .001), higher 90-day mortality (odds ratio = 8.1, 95% CI = 3.0 to 35.4; P < .001), and lower overall response rate (odds ratio = 0.4, 95% CI = 0.2 to 0.8; P = .019). The PM-IPI retained prognostic ability in both validation cohorts and performed better than previously published phase I prognostic scores for predicting OS in all three cohorts. Conclusions: The PM-IPI is a validated prognostic score for patients treated in phase IIO trials and may aid in improving patient selection.