bluuebunny/crossref_metadata_2025 huggingface dataset:
Breath biopsy early detection of lung cancer using an EVOC probe targeting tumor-specific extracellular β-glucuronidase.
Authors: Labuschagne Christiaan Frederick , Smith Rob , Kumar Neelam , Allsworth Max , Boyle Billy , Janes Sam , Crosbie Phil , Rintoul Robert
Published: June 2022

2569

Background: Lung cancer is a leading cause of mortality with 5-year survival less than 20%, largely a result of many cases being diagnosed late. Early detection can increase cancer survival up to 13-fold underscoring the need for effective screening. Targeted Low dose computed tomography (LDCT) has been shown to be effective but its impact to date has been limited due to slow adoption and variable uptake in high-risk populations. Breath analysis represents a non-invasive screening approach either alone or alongside LDCT. Numerous studies have investigated potential endogenous breath biomarkers of lung cancer. Many have produced promising results but to date, no validated biomarkers with clear connections to cancer metabolism have been revealed. We have explored an alternative, probe-based approach based around Exogenous Volatile Organic Compound Probes (EVOC Probes). The probes target tumour associated extracellular b-glucuronidase, a glycosidase enzyme that normally resides within lysosomes. Methods: We use a hydrophilic non cell permeable substrate probe D5-ethyl-βD-glucuronide (D5-EtGlu) that upon hydrolysis by the target enzyme releases D5-ethanol, a unique volatile reporter molecule detectable on breath. This provides a readout of tumour associated enzyme activity using breath analysis. Results: Administering D5-EtGlu to mice resulted in tumour specific release of D5-ethanol, enabling discrimination between healthy and tumour bearing animals. Increased expression of b-glucuronidase in lung cancer tissue and the tumour microenvironment was confirmed with immunohistochemistry (IHC) in clinical samples. A phase 1a clinical trial administered D5-EtGlu to healthy individuals in a single ascending dose study to establish safety and background D5-ethanol levels in healthy individuals. This resulted in no adverse events and low/no D5-ethanol signal verifying the inaccessibility of D5-EtGlu to intracellular b-glucuronidase. The next stage, currently ongoing, is a proof of mechanism in humans. D5-EtGlu is administered intravenously to confirmed lung cancer patients followed by breath analysis. D5-ethanol breath levels will be compared to cancer free individuals receiving the same dose of D5-EtGlu. Conclusions: Non-invasive breath testing has great potential to contribute to diagnosis for lung cancer including a potential role in screening. Our current work is evaluating the use of an administered probe to stimulate tumour-specific enzyme activity and produce a marker detectable on breath. Continued success could result in a sensitive and highly specific method for lung cancer early detection.
Phase I study of epacadostat in combination with sirolimus in advanced malignancy.
Authors: Huang Chao Hui , Komiya Takefumi , Kasi Anup , Williamson Stephen K. , Baranda Joaquina Celebre
Published: June 2022

2575

Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients with advanced solid tumors, with plans for an expansion phase II study in patients with advanced recurrent lung cancer once maximum tolerated dose (MTD) was defined. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at day -7 followed by 1mg/d with E added on day 1 of Cycle 1 starting at 300mg bid in a 28d cycle at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400 bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. Enrollment continued until Dose limiting toxicity (DLT) which was defined as grade 3 hematologic toxicities or grade 3 or 4 non-hematologic toxicities up to Cycle 2 day 1. MTD was defined as DLT not exceeding 33% of subjects. Results: The phase I study enrolled 15 patients, with 9 patients evaluable. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). DLT was not observed up to level 3. Adverse events attributed to SE were Grade 1 Diarrhea (2), stomach pain (1); elevated liver enzymes (ELE) (1), decreased white blood cell (1), anorexia (1), hypokalemia (1), dizziness (1), skin rash (1); Grade 2 ELE (1), Anemia (1), Vertigo (1), Constipation (1), Nausea (2); Grade 3: Diarrhea (1), serotonin syndrome (1), dyspnea (1). The best response observed was stable disease in 3 patients, 5 patients had disease progression and 1 patient was not assessable for response due treatment discontinuation related to side effect of serotonin syndrome. The Expansion Cohort (Part 2) did not proceed since the sponsor decided to discontinue further development of E. Conclusions: The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities. There were few grades 3 toxicities. SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer resistant to checkpoint inhibitor is worth additional exploration. Clinical trial information: NCT03217669.
Factors associated with acute kidney injury among patients with cancer treated with immune checkpoint inhibitor therapy: A population-based study.
Authors: Blanchette Phillip S. , Richard Lucie , Shariff Salimah , Raphael Jacques , Earle Craig , Garg Amit , Kitchlu Abhijat
Published: June 2022

2584

Background: Cancer immune checkpoint inhibitor (ICI) therapy may be associated with kidney immune-related adverse events (IRAEs) and other causes of acute kidney injury (AKI). In clinical trials, the frequency of AKI events was uncommon, however, further real-world study is warranted. Methods: We evaluated the proportion of AKI events among patients with advanced cancer (bladder, head and neck, lung, kidney and malignant melanoma) treated with ICI therapy in Ontario, Canada from 2012 - 2018. AKI was defined by a rise in the concentration of serum creatinine as per Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A multivariable regression model was used to identify predictors of AKI while accounting for the competing risk of death. Results: A total of 4,380 patients received ICI therapy. In follow-up, 1,283 (29%) had recorded AKI event (any stage AKI) and 289 (7%) had a severe AKI event (≥ stage 2). Median time to AKI was 6 months (Interquartile Range 2-16 months) and ≤ 1 % of patients received dialysis therapy. Within 30 days of any observed AKI event, 853 (58%) discontinued ICI therapy, 372 (29%) were hospitalized and 266 (21%) died. Mortality was significantly higher among patients who experiencing a severe AKI event (≥ stage 2) as compared to patients with a less severe AKI event (stage 1) or no observed AKI event. Among patients alive at 30 days following an AKI event, 14% received an outpatient corticosteroid or immunosuppressive therapy prescription, 7% had a visit with a nephrologist. Characteristics associated with a higher risk of AKI included female sex, bladder or kidney cancer (reference malignant melanoma), history of hypertension or diabetes, higher Charlson comorbidity score, a baseline estimated glomerular filtration rate less than 30 mL/min/1.73 m2, or outpatient prescription for either a proton pump inhibitor or non-steroidal anti-inflammatory drug. Among patients with an AKI event and treatment discontinuation, re-challenge of ICI therapy was infrequent (16%) with a significant risk of a recurrent AKI event (57%). Conclusions: In a population-based study among patients with cancer receiving ICI therapy, the rate of AKI was common (29%) but severe AKI was less frequent (7%). Rates of ICI discontinuation, hospitalization and death are substantial following an AKI event. Kidney function should be monitored carefully among patients undergoing ICI therapy who have common risk factors for developing renal disease. Nephrology consultation may be optimized among patients who develop a severe AKI event, especially among individuals who are considered for ICI therapy re-challenge.
Preliminary data from an ongoing phase 1 dose-escalation study of CCX559, an orally administered small molecule PD-L1 inhibitor, in patients with advanced solid tumors.
Authors: Tapia Gonzalo , Lundy Joanne , Richardson Gary Edward , Zhao Niky , Ebsworth Karen , Yue Huibin , Miao Shichang , deGoma Emil , Jain Rita , Schall Thomas J. , Sullivan Kathleen , Zhang Penglie , de Souza Paul L.
Published: June 2022

2593

Background: The novel small molecule CCX559 is a highly potent and selective PD-L1 inhibitor that induces the dimerization and internalization of cell-surface PD-L1. CCX559, when orally administered in animal models, demonstrated anti-tumor efficacy, including the ability to induce complete responses (Li C, et al. Cancer Res 2021;81(13_Suppl): Abstract nr 1274). Safety pharmacology and toxicology studies in animals demonstrated an acceptable safety profile for CCX559. Taken together, the preclinical data supports the initiation of human trials in patients with advanced solid tumors. PD-(L)1 therapies have been shown to increase peripheral T cell activation and cytokines such as IFNγ and CXCL9 in patients (Herbst RS, et al. Nature.2014; 515(7528):563–567). Methods: This phase 1, first-in-patient, multicenter, open-label, dose-escalation study evaluates safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of CCX559 in patients with refractory, locally advanced or metastatic solid tumors. CCX559 is dosed orally once daily with a starting dose level of 30 mg. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design. PBMC and plasma samples were collected from patients over the first 2 cycles (6 weeks) of treatment, and PD assays were performed, including measurement of cytokines and T cell proliferation. Results: As of February 1, 2022, one patient per cohort was enrolled at the 30 mg and 60 mg levels, and 9 patients were enrolled in the 120 mg dose cohort. Of the 11 patients enrolled, 5 patients (all 120 mg cohort) remain on treatment. No DLTs, treatment-related SAEs, or severe (Grade 3 or higher) treatment-related AEs have been reported. PD assays have been performed with samples from the 30 mg (n=1), 60 mg (n=1), and 120 mg (n=3) cohorts. Patients in all three cohorts showed increased peripheral CD4 and CD8 T cell proliferation starting in the first cycle (21 days) of treatment, as measured by Ki67 positivity. Increases in plasma IFNγ, CXCL9, CXCL10, and CXCL11 levels were observed, in particular in one patient (120 mg cohort) starting 15 days after treatment initiation. Conclusions: Initial results from the phase 1 dose-escalation study of CCX559 indicate on-target PD effects consistent with PD-L1 inhibition. Updated PD data, together with the safety and PK profile, will be presented. Clinical trial information: ACTRN12621001342808.
Cancer PD1/PD-L1 inhibitor efficacy as stratified by smoking status: A population large database study.
Authors: Urdang Zachary D. , Park SoHye , Philips Ramez , Juon Hee-Soon , Johnson Jennifer Maria , Martinez-Outschoorn Ubaldo E. , Curry Joseph M.
Published: June 2022

2594

Background: Delineating clinical factors that predict immune checkpoint inhibitor (ICI) cancer therapy response is a pressing need and smoking is a known factor. In this study we leveraged a large international (heavily US) database to perform the largest study to date for all cancers and major cancer sub-sites/types. Methods: Utilizing the TriNetX electronic health records database with 84.3M patients we tested the hypotheses that ICI response stratifies based on smoking, and continued smoking after ICI. Queries were constructed using billing codes for all cancer types treated with an ICI with and without smoking. The smoking cohort was subsequently sub-stratified for continuing vs cessation of smoking after ICI. Next, using ICI therapy as the index event, odds ratios (OR) with 95% confidence intervals for death, and treatment related secondary outcomes were calculated between 0.5-5 years after ICI treatment. Statistics were calculated using TriNetX's integrated statistical platform before and after 1:1 propensity score matching (PSM) for smoking related co-morbidities. Results: The OR for death after ICI therapy for smokers ( n 13336) vs non-smokers ( n 38973) for any cancer type was 1.27(1.21-1.34) and decreased to 1.11(1.04-1.19) after PSM. Further sub-stratifying the smoking cohort for continued vs cessation of smoking yielded ORs of 1.13(1.03-1.24) and 1.12(1.01-1.24) before and after PSM respectively. Secondary outcomes included ablative surgery, chemotherapy, radiation, and secondary neoplasm. ORs for receiving chemotherapy, and developing secondary neoplasm were most consistently statistically significant across comparisons. Conclusions: Smoking adversely potentiates cancer outcomes after ICI therapy. PSM for smoking related comorbid conditions decreased the magnitude of this association although the findings remained clinically and statistically significant. This highlights the key role in smoking related co-morbid conditions as prognostic clinical characteristics. Furthermore, this suggests that smoking affects ICI on a mechanistic/biological level beyond increasing burden of medical comorbidities. Lastly, as smoking cessation also improved outcomes after PSM this further suggests that washout of smoke toxins has a mechanistic/biological effect on ICI activity. [Table: see text]
Identification of super-exhausted T cells: A novel population predictive of response to immunotherapy.
Authors: Peyraud Florent , Guegan Jean-Philippe , Rey Christophe , Cousin Sophie , Roubaud Guilhem , Cabart Mathilde , Brunet Maxime , Oflazoglu Gruyters Ezogelin , Savina Ariel , Le Moulec Sylvestre , Dadone-Montaudon Bérangère , Barlesi Fabrice , Besse Benjamin , Loriot Yohann , Marabelle Aurelien , Soria Jean-Charles , Scoazec Jean-Yves , Le Loarer François , Bessede Alban , Italiano Antoine
Published: June 2022

2596

Background: Given that most of cancer patients treated with anti-PD1/PD-L1 immune checkpoint blockers (ICB) do not derive benefit, there is a crucial need to identify reliable predictive biomarker of response. Besides PD-1, several key immune checkpoints, such as CTLA4, LAG3, TIM3 and TIGIT, are associated with a T cell exhausted phenotype and play a crucial role in leading to cancer immune evasion. The impact of simultaneous expression by T cells of distinct inhibitory receptors on outcome of patients treated with ICB is still unknown. Methods: We analyzed the tissue samples, collected before ICB initiation, from patients with solid tumors and included in an institutional molecular profiling program (NCT02534649). We used multiplexed-immunohistofluorescence with the following panel CD3/PD1/TIM3/LAG3/TIGIT/CTLA4, and performed immune cell characterization using multispectral images analysis. We then investigated the correlation between coexpression of T cell-associated exhaustion markers, clinical response rate, progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards models. Results: Four hundred thirty five patients were included in the analysis (NSCLC: n=207, 47.6%; sarcoma: n=42, 9.7%; urothelial: n=30, 6.9%; others: n=156, 35.9%). Digital pathology analysis allowed us to identify a population of “super-exhausted” T cells characterized by the co-expression of PD1, LAG3, TIGIT and TIM3 which was enriched in 125 cases (28.7%), and was significantly associated with better PFS (HR 1.60, CI95 1.26-2.04, p<0.001) and OS (HR 1.42, CI95 1.07-1.89, p=0.016) in the whole cohort. Patients with super-exhausted high tumors had higher objective response rate (38.4%) compared to super-exhausted low tumors (19.7%, p<0.001). The presence of super-exhausted T cells was significantly higher in responders (10%) versus non responders (4%, p<0.001). Correlation with better outcome was observed whatever the subgroup considered (NSCLC vs other tumors, CD8 T cells density and presence of tertiary lymphoid structure [TLS]). In multivariate analysis (n=372, 85.5%), increased tumor infiltration by super-exhausted T cells (>1 %) was significantly associated with better PFS (HR 0.61, CI95 0.46-0.81, p<0.001, Table) and OS (HR 0.68, CI95 0.48-0.97, p=0.033, Table). Conclusions: The presence of super-exhausted T cells may represent a new predictive biomarker of response to ICB and pave the way for the development of effective ICB combinations. Data from an independent validation cohort will be presented at the meeting. [Table: see text]
Association between body mass index and treatment efficacy with immune checkpoint inhibitor therapy: A retrospective study.
Authors: Wang Hannah , Ali Atif , Prather Lyndsey L , Du Wendy , Chen Nan , Sheth Aakash , Sandulache Vlad , Sabichi Anita Lyn , Wang Daniel Ying , Kemnade Jan Ole
Published: June 2022

2598

Background: Increased body mass index (BMI) has been associated with improved efficacy of immune checkpoint inhibitor therapy (ICI) in cancer patients. We aimed to retrospectively assess the relationship between patient BMI and response to ICI at two unique health care systems in our institution Methods: We identified patients treated with ICI from 2015-2021 at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) Cancer Center and Baylor St. Luke’s Medical Center (BSLMC), a private hospital-based cancer center, both academic affiliates of Baylor College of Medicine. Clinical details, including BMI, and treatment efficacy were collected. We defined BMI categories as follows: underweight ( < 18.5), normal weight (18.5-24.9), overweight (25-29.9), and obese (≥30). Progression free survival (PFS), overall survival (OS), and overall response rate (ORR) were the primary end points calculated for treatment efficacy. Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with log-rank test. Cox regression analysis was used to determine whether BMI at ICI initiation was associated with survival. Chi-square testing was used to determine any association between BMI and ORR. Results: We identified 430 patients treated with ICI, 257 (60%) from BSLMC and 173 (40%) from MEDVAMC. 341 patients (79%) were male and 89 (21%) female. Cancer types included 127 (30%) lung, 49 (11%) kidney, 40 (9.3%) bladder, 38 (8.8%) melanoma, and 38 (8.8%) mesothelioma, 34 (7.9%) head and neck, and 104 (24%) other. 160 (37%) patients had a normal BMI at ICI initiation, 37 (8.6%) underweight, 132 (31%) overweight, and 101 (23%) obese. Mean BMIs of different cancer types were as follows: lung (24.7), kidney (29.2), bladder (26.0), melanoma (29.9), mesothelioma (25.25), head and neck (23.7). 292 (68%) patients were treated with ICI monotherapy. The ORR for patients with normal vs. obese BMIs treated with ICI were 28% and 42%, respectively (p = 0.03). In a subset of patients evaluable for survival (n = 322), patients with an obese BMI had a significantly improved median PFS compared to those with normal BMI (36.4 vs. 23.5 months, respectively, p < 0.0001). Multivariable analysis demonstrated that patients with an obese BMI had significantly improved overall survival compared to patients with a normal BMI (HR 0.64, 95% CI 0.44-0.91, p = 0.014). This relationship was also seen in the subset of patients treated with ICI monotherapy (HR 0.66, 95% CI 0.45-0.95, p = 0.029). This association was noted regardless of health care systems. Conclusions: Increased BMI in cancer patients treated with ICI may predict better treatment efficacy and survival outcomes. More research is needed to define this relationship more clearly.
A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb), in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.
Authors: Ganju Vinod , Cooper Adam , Gao Bo , Wilkinson Kate
Published: June 2022

2602

Background: YH001 is a humanized anti-hCTLA-4 IgG1 mAb that relieves CTLA-4-mediated immunosuppression, and thereby enhances the T-cell-mediated antitumor immune response. Pre-clinical data have shown potent anti-cancer activity when combined with anti-PD-1 mAb. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia. Patients (pts) with advanced solid tumors received YH001 by IV administration at 0.05 to 6.0 mg/kg for 1 cycle (21 days) then in combination with Toripalimab (anti-PD-1 mAb) at 240 mg Q3W for 4 cycles. An accelerated titration method followed by the standard "3+3" design was utilized to evaluate safety, tolerability and preliminary efficacy. Results: As of 31-Dec-2021 data cut-off, 24 pts with advanced solid tumors were enrolled and dosed at 0.05 mg/kg (n=2), 0.1 mg/kg (n=3), 0.3 mg/kg (n=3),1mg/kg (n=5), 2mg/kg (n=5), 4mg/kg (n=3) and 6mg/kg (n=3). Baseline ECOG scores were 0 (n=14), 1 (n=10) with all pts progressed after a median of 2 prior lines of available standard therapy (range 1-5) including 5 pts progressed after prior immunotherapy of anti-PD-1 antibody. Overall, 6 cases of Grade(G) 3 or above treatment-related AEs (TRAEs) have been reported in 5 pts at 0.3 mg/kg, 4 mg/kg and 6 mg/kg dose level respectively, including 1 G3 colitis, 1 G4 thrombocytopenia, 1 G3 Enterocolitis, 1 G3 Rash, 1 G3 Pruritus and 1 G3 hepatitis. There were no death events due to TRAEs. 18 pts (75%) had 63 TRAEs of any level, including 28 G1 TRAEs, 29 G2 TRAEs. 2 of the first 3 pts at MAD (6mg/kg) met protocol defined DLT in Combo phase. Among the 23 pts having imaging tumor assessment by RECIST v1.1, 4 achieved PR and 9 achieved SD in Best of Response. 1 subject with gastroesophageal junction carcinoma at 0.3 mg/kg has achieved PR since the 2nd tumor assessment, target lesion decreased by up to 84.5% from baseline. 1 subject with urothelial carcinoma at 2 mg/kg progressed after prior anti-PD-1 antibody has achieved PR since the 2nd tumor assessment, target lesion decreased by up to 74% from baseline. 1 subject with uterine carcinosarcoma at 2 mg/kg has achieved PR since the 1st tumor assessment, target lesion decreased by up to 52.3% from baseline. 1 subject with vulva adenocarcinoma at 6 mg/kg has achieved PR since the 1st tumor assessment, target lesion decreased by up to 71.4% from baseline. ORR (CR+PR) and DCR (CR+PR +SD) were 17.4%, 56.5% respectively. Conclusions: YH001 was well tolerated up to 4 mg/kg dose levels when combined with toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04357756.
Retrospective analysis of the effect of angiotensin receptor blockers and angiotensin converting enzyme inhibitors on the efficacy of anti-PD-1/PD-L1 immunotherapy in patients with advanced cancer.
Authors: Suh Jason , Rutledge John R. , Friedlander Philip Adam
Published: June 2022

2605

Background: Components of the renin angiotensin system (RAS) are expressed in tumors with activation leading to tumor and stromal cell release of immunomodulatory cytokines promoting an immunosuppressive microenvironment and increased infiltration of tumor associated macrophages. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are anti-hypertensives that inhibit the RAS. It is unknown if ACEi and ARB treatment modulates the efficacy of anti-PD-1/PD-L1 immunotherapy. Methods: A retrospective chart review was conducted to identify patients with unresectable malignancies initiating treatment with a PD-1 or PD-L1 inhibitor based regimen between 1/1/13 and 6/1/19 at Valley Hospital in New Jersey. IRB approval was obtained. Efficacy of treatment was measured by medical oncologist documentation of clinical benefit (CB = stable disease / treatment response) versus disease progression. Chi-square tests were performed to assess relationship between ACEi or ARB exposure and immunotherapy benefit. To assess for a broader anti-hypertensive effect, the relationship in patients on a beta-blocker but not ACEi/ARB was assessed. Results: 197 patients were identified of which 190 had documentation of clinical outcome. The mean age was 72.8 years with 54% female and 46% male. 56 patients were exposed to ACEi (N = 28) or ARB (N = 28) and 141 patients to neither. 37 patients were exposed to beta blocker but not ACEi or ARB. 60 patients had nonsquamous NSCLC (16 on ACEi or ARB), 26 squamous NSCLC (7 on ACEi or ARB) and 24 melanoma (10 on ACEi or ARB). 71% of ACEi/ARB exposed patients had CB by clinician assessment as opposed to 47% in those not on ACEi or ARB (p = 0.003). In ACEi exposed patients, 71% had CB versus 51% in unexposed patients (p = 0.048). In ARB exposed patients, 70% had CB versus 51% in unexposed patients (p = 0.069). By contrast, 51% of beta-blocker treated patients had CB versus 55% in untreated patients (p = 0.72). 36% of ACEi/ARB exposed patients remained on treatment at 12 months versus 22% of ACEi/ARB unexposed patients. Subset analyses were performed on the 3 largest patient populations: squamous NSCLC, nonsquamous NSCLC and melanoma. ACEi/ARB exposed melanoma patients had CB rate of 70% versus 43% in those unexposed. ACEi/ARB exposed squamous NSCLC patients had CB rate of 86% versus 47% in unexposed patients. By contrast, ACEi/ARB exposed nonsquamous NSCLC patients had a 56% CB rate versus 48% in unexposed patients. Conclusions: Based on retrospective analysis, advanced cancer patients treated with anti-PD-1/PD-L1 regimens had a statistically significant increase in clinical benefit if administered in the context of renin angiotensin system blockade. Prospective disease specific trials can further validate these findings and define the degree of clinical benefit.
Predictors of response to immune checkpoint inhibitors (ICI) rechallenge post-disease progression in solid tumors: A systematic review and meta-analyses.
Authors: Abushukair Hassan Mohammed , Al-Kraimeen Leen Mohammad , Saeed Anwaar
Published: June 2022

2612

Background: Rechallenge with the same or different ICI has been proposed as a second line option in patients who progress on an initial ICI course. Considering rechallenge risks of limited benefit and further toxicity, identifying predictors for patients benefiting from rechallenge would provide much needed guidance for practice. We present a systematic review and meta-analyses of response predictors to ICI rechallenge after disease progression in solid tumors. Methods: A systematic search of PubMed, Cochrane database and ASCO meeting library was done for studies published up to Jan 2022 evaluating the efficacy of ICI rechallenge in patients with advanced solid tumors after disease progression on initial ICI. Predictors of interest included duration of the initial ICI course using a cutoff point of 6 months, and best overall response (BOR) to initial ICI: stratified into responders (complete or partial response or stable disease) and non-responders (progressive disease). Odds ratios (OR) for ICI rechallenge response were calculated & pooled in reference to initial ICI duration and its BOR using the fixed effects model. ORs with a 95% confidence interval [CI] not overlapping the null value (1) were considered statistically significant. Results: A total of 56 studies reporting on ICI rechallenge upon progression, comprising 3579 patients, of which 31 studies have switched their second ICI regimen. Initial ICI was anti-PD-1 in 37 studies, anti-CTLA-4 in 14 studies, and anti-PD-L1 in 10 studies. Involved solid cancers included melanoma (n = 30), NSCLC (n = 15), RCC (n = 6), and others (n = 5). Pooled objective response rate for rechallenge was 18.4% ([15.4-21.4], I2 = 84.6%), with the highest being among melanoma patients (21.2% [17.2-25.2], I2= 83.4%). For BOR, no significant difference was found for the entire cohort (OR = 1.34 [0.86 - 2.09], I2 = 27.1%). In melanoma studies, response to ICI rechallenge was significantly higher in patients responding to the initial ICI prior to progression (OR = 1.87 [1.03-3.39], I2 = 24.5%). For treatment duration, there was no difference in the entire cohort concerning ICI rechallenge (OR = 1.54 [0.86-2.75], I2 = 14.2%), yet melanoma patients showed a significant difference favoring those who had longer response durations on initial ICI (OR = 2.05 [1.01-4.16], I2 = 0.0%). Conclusions: Response to rechallenge in advanced melanoma patients was more common in initial ICI responders with a longer course duration ( > 6 months). More homogeneous studies are needed to validate our findings and investigate other potential markers for rechallenge such as PD-L1 status & mutational burden. [Table: see text]
Association of proton pump inhibitor use with survival outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Chen BaoQing , Yang Chen , Dragomir Mihnea-Paul , Chi Dongmei , Chen Wenyan , Calin George , Li Qiaoqiao
Published: June 2022

2613

Background: Proton pump inhibitors (PPIs) were revealed to regulate gut microbiome alterations and further impact the response to immune checkpoint inhibitors (ICIs). Contradictory impacts on survival were observed in ICI-treated patients when concomitantly use PPI or not. We performed this systematic review and meta-analysis to analyze the association of PPI use with survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases and major oncology conferences proceedings were comprehensively searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI use and PPI non-use in ICI-treated cancer patients were included. Data regarding the characteristics, ICI and PPI treatments and survival outcomes for patients were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effect models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among study results. Results: A total of 20 studies were included, comprising 2812 ICI- and PPI-treated patients and 3990 ICI-treated and PPI-free patients. The pooled HR is 1.30 (95% CI, 1.17-1.45; P <.001) for OS and 1.20 (95% CI, 1.08-1.34; P <.001) for PFS, indicating a significant negative association between PPI use and survival of ICI-treated patients. Subgroup meta-analyses by factors including cancer types, ICI types and time window of PPI use, revealed such associations were in patients with non-small cell lung cancer (OS: HR = 1.40, 95% CI = 1.23 to 1.59, P <.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P <.001) or urothelial cancer (OS: HR = 1.50, 95% CI = 1.26 to 1.80, P <.001; PFS: HR = 1.37, 95% CI = 1.17 to 1.60, P <.001), patients treated with anti-PD-1/PD-L1 (OS: HR = 1.41, 95% CI = 1.30 to 1.53, P <.001; PFS: HR = 1.29, 95% CI = 1.20 to 1.38, P <.001), patients receiving PPI as baseline treatment (OS: HR = 1.43, 95% CI = 1.21 to 1.69, P <.001; PFS: HR = 1.29, 95% CI = 1.16 to 1.44, P <.001) or 60 days before ICI treatment initiation (OS: HR = 1.28, 95% CI = 1.11 to 1.48, P <.001; PFS: HR = 1.27, 95% CI = 1.16 to 1.40, P <.001), rather than concomitantly with ICI initiation. Conclusions: PPIs use in patients treated with ICIs is associated with a shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled, and appear to not impact survival if given temporarily after ICIs initiation. These detailed observations could provide basis for clinical guidelines when concomitantly use PPIs and ICIs.
Analysis of the contribution of macrophages to the overall tumor PD-L1 microenvironment using a screening multi-tumor tissue microarray and rapid multiplex fluorescence digital phenotyping approach.
Authors: Cumberbatch Marie , Wood Douglas , Chatterjee Gourab , Womack Christopher , Bhagat Milan , Sherry Lorcan
Published: June 2022

2620

Background: Programmed death ligand-1 (PD-L1) contributes to immune suppression in the tumor microenvironment (TME) by interacting with programmed cell death-1 (PD-1) on infiltrating T lymphocytes leading to tumor immune escape. Application of omics technologies has shed light on the relevance of the TME for response to immunotherapies and development of novel treatment options. Here we have applied a multi-plex immunofluorescence/multi-tumor tissue microarray (TMA) approach to examine the immunobiology of different TMEs with respect to the contribution by tumor cells and macrophages to overall PD-L1 expression. Methods: A TMA comprising 11 tumor types and a total of 144 different donors, each represented by two cores [1mm; 1 from invasive margin (IM) and 1 from tumor center (TC)], was stained using Ultivue’s Immuno8 FixVUE panel (CD3, CD4, CD8, FOXP3, CD68, PD-1, PD-L1, pan-CK/SOX10). Whole slide images from two rounds of imaging (x20 magnification; four markers in each round) were aligned using Ultivue's UltiStacker software based on the nuclear counterstains from the two imaging rounds, to provide precise marker colocalization data. Cell phenotype data for each core was generated using Visiopharm software. Results: Overall PD-L1 positivity was greatest for NSCLC, SCLC, TNBC and gastric cancer ranging from approximately 600-1000 PD-L1+ cells/mm2/core, compared with CRC, breast, pancreatic, liver, and gastric esophageal junction (GOJ) cancers (approx. 50-300 PD-L1+ cells/mm2/core). Contribution by macrophages to overall PD-L1 expression (dual CD68+/PD-L1+) varied by tumor type representing 25-35% for NSCLC (SCC and ADC) and gastric cancer, whereas a converse pattern was apparent for SCLC, TNBC, breast (ER+ and Her2+) and pancreatic cancers where PD-L1+ macrophages accounted for a large proportion (approx. 60-85%) of overall tumor PD-L1 expression. Interestingly, as a proportion of total macrophage infiltration, approximately 65% of CD68+ macrophages were PD-L1+ for SCLC and TNBC, compared with less than 10% for pancreatic and liver cancer. Spatial analysis revealed PD-L1+ macrophage infiltration to be generally higher for IM versus TC, and the distribution between tumor (CK+) and stroma (CK-) remained similar despite exclusion of CD3+/CD8+ cytotoxic T cells from CK+ tumor regions for pancreatic and liver cancer. Conclusions: Taken together, these data illustrate the benefits of combining multiplexed immunofluorescence staining, with digital analysis of cell phenotypes within well characterized tumor samples to better understand the relative immunobiology of different TMEs. Here we demonstrate that the relative contribution of macrophages to the overall PD-L1 microenvironment varies between tumor types, which may help guide options for successful immunotherapy strategies.
Correlation between MSI, TMB, and RAS gene mutation in solid tumors.
Authors: Li Qingchang , Bian Zhengying , Ma Juan , Lu Guanghua , Chen Siqi , Ding Ran , Bu Fanfeng
Published: June 2022

2624

Background: RAS gene family encodes a protein that is a member of the small GTPase super family and plays an important role in the regulation of cell proliferation and promoting oncogenic events. Studies have reported that RAS gene shows a high mutation frequency in lung cancer, colorectal cancer and pancreatic cancer. However, the relation between RAS-mutant and RAS-wild type tumors in tumor mutation burden (TMB) and microsatellite instability (MSI) remain unclear in pan-cancer. Methods: We retrospectively analyzed 15188 Chinese patients with pan-cancer from laboratory of Simcere Diagnosis (Nanjing, China) during 2019-2021. Somatic mutations in tumor samples were assessed by next-generation sequencing (NGS). We evaluated RAS (KRAS, NRAS and HRAS) mutation frequency, TMB and MSI in RAS-mutant and RAS wild-type tumors. Results: RAS mutations were detected in 2663 (17.5%) samples, including 88.7% of KRAS mutations, 9.1% of NRAS mutations and 3.5% of HRAS mutations. The top 6 frequently cancers were colorectal cancer (829, 31.1%), lung cancer (747, 28.1%), pancreatic cancer (358, 13.4%), biliary tract cancer (210, 7.9%), liver cancer (78, 2.9%), and gastric cancer (73, 2.7%). We found that the incidence of MSI-H in patients with RAS-mutant solid tumors was 3.3% and the frequency of MSI-H was significantly higher in RAS-mutant gastric cancer than that in RAS wild-type (RAS-MUT vs RAS-WT, 20.5% vs 3.5%, p < 0.001). Contrary to our assumption, it was not observed in colorectal cancer (RAS-MUT vs RAS-WT, 5.8% vs 6.9%). In the analysis of TMB, RAS gene mutation was associated with higher TMB (P < 0.01). 27.4% of RAS-mutant gastric cancer and 10.8% RAS wild-type gastric cancer were classified as TMB-H (TMB ≥10 muts/Mb) (P＜0.01), while 13.4% of RAS-mutant colorectal cancer was TMB-H, with no significant difference between RAS wild-type. However, we did not observe a close association between MSI, TMB and RAS gene mutations in lung cancer, pancreatic cancer, biliary tract cancer, and liver cancer. Conclusions: We analyzed RAS gene mutations in Chinese patients with solid tumor. Our data showed that RAS mutations were associated with TMB-H and MSI-H in solid tumors, especially gastric cancer. In colorectal cancer, RAS mutations were associated with higher TMB, but not TMB-H. It was showed that RAS mutations in specific cancer types, such as gastric cancer and colorectal cancer, may be related to the efficacy of immunotherapy.
14-gene immunoglobulin (IGG) and proliferation signatures and association with overall survival across cancer-types.
Authors: Schettini Francesco , Paré Laia , Marín-Aguilera Mercedes , Puig Susana , Mezquita Laura , Baste Neus , Pascual Tomás , Martinez Saez Olga , Conte Benedetta , Jares Pedro , Puig-Butillé Joan Anton , Sanfeliu Torres Esther , González-Farre Blanca , Villagrasa Patricia , Conte Pier Franco , Perou Charles , Parker Joel S. , Brasó Maristany Fara , Prat Aleix
Published: June 2022

2636

Background: The HER2DX prognostic assay in early-stage HER2-positive breast cancer integrates clinical variables and 4 gene expression signatures (GES) tracking IGG, tumor proliferation, luminal cell differentiation, and the expression of the HER2 amplicon. Here, we assessed the prognostic value across cancer-types of each of these four individual GES and a research-based version of the HER2DX risk-score. Methods: RSEM batch normalized RNA-sequencing gene expression data from The Cancer Genome Atlas (TCGA) project were downloaded from cBioPortal. The association between a research-based version of the HER2DX risk-score, and each GES, with overall survival (OS) was assessed as continuous variables using univariate Cox regression model. The research-based version of the HER2DX risk-score tested did not include clinical variables. The Cox model was applied to estimate hazard ratios (HR) with 95% confidence intervals. The threshold for statistical significance was set at p< 0.05. Results: Gene expression data from 9,852 patients representing 30 different cancer-types were evaluated. The proliferation, IGG, luminal and HER2 amplicon GES were significantly associated with OS in 40.0%, 33.3%, 23.0% and 6.7% of the cancer-types tested, respectively. The IGG GES was found significantly associated with a favorable OS in breast cancer (HR: 0.73, p < 0.001), cervical and head & neck squamous cell carcinomas (HR: 0.75, p = 0.021 and HR: 0.78, p < 0.001), lung adenocarcinoma (HR: 0.84, p = 0.020), skin melanoma (HR: 0.73, p < 0.001) and sarcomas (HR: 0.78, p = 0.029). Conversely, association of IGG GES with unfavorable OS was observed in uveal melanoma (HR: 1.74, p = 0.008), kidney clear cell and papillary cell carcinomas (HR: 1.29, p < 0.001 and HR: 1.44, p = 0.017, respectively), as well as brain low-grade gliomas (LGG) (HR: 1.56, p < 0.001). Finally, the research-based HER2DX risk-score was found significantly associated with OS in 11 of 30 (36.7%) cancer-types, including breast (HR: 1.42, p < 0.001) cervical and head & neck squamous cells cancers (HR: 1.36, p = 0.018 and HR: 1.30, p < 0.001), lung adenocarcinoma (HR: 1.34, p < 0.001), skin melanoma (HR: 1.34, p < 0.001), sarcomas (HR: 1.41, p = 0.003), adrenocortical carcinoma (HR: 2.31, p < 0.001), endometrial carcinoma (HR: 1.36, p = 0.005), hepatocarcinoma (HR: 1.26, p = 0.012), LGG (HR: 1.37, p = 0.001) and mesothelioma (HR: 1.48, p = 0.005). Conclusions: The 14-gene IGG and proliferation signatures are strong prognostic biomarkers across cancer-types. The opposite association of IGG with OS depending on the cancer-type warrants further investigation.
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting multifunctional immune-recruitment protein, in patients with advanced solid tumors.
Authors: Luke Jason J. , Saeed Anwaar , Bashir Babar , Shwartz Yaffa , Tabakman Rinat , Foley-Comer Adam , Jimeno Antonio
Published: June 2022

2647

Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.
A phase 1a dose-escalation study of PY314, a TREM2 (Triggering Receptor Expressed on Macrophages 2) targeting monoclonal antibody.
Authors: Patnaik Amita , Hamilton Erika P. , Winer Ira Seth , Tan Winston , Hubbard Joleen M. , Schenk Erin Lynn , Sonbol Mohamad B. , Jahchan Nadine , Pierce Kristen , Li Yunfeng , Reyno Len , Chamberlain Marc
Published: June 2022

2648

Background: To characterize the safety and tolerability of PY314, an immunosuppressive macrophage depleting antibody, as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors including subject’s refractory to checkpoint inhibitors if approved for that indication. Methods: Two were evaluated in subjects with advanced solid tumors, single agent PY314 and PY314 in combination with 200 mg of pembrolizumab using a 3+3 dose escalation study design. Dosing was intravenous and administered once every 3-weeks, a defined cycle. Disease assessment by RECIST 1.1 was performed every 6 weeks. Each stratum included 4 dose levels of PY314 (1, 3, 10, and 20 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM2 expression by immunohistochemistry. Based on preclinical evaluation of TREM2 expression, HR+ HER2- and triple negative breast cancer, colorectal cancer, renal cell cancer, non-small cell lung cancer and gynecologic cancers were studied. Results: 28 subjects (median age 60 years [range 26-76], 22 females and 6 ) with an ECOG PS <2 were enrolled and all, but one was (1 subject withdrew consent after dosing). 15 subjects were treated with single agent PY314 and 13 were treated with the combination. No infusion-related reactions, dose limiting toxicities, suspected unexpected serious adverse reactions or high-grade treatment related adverse events (TRAEs) that resulted in treatment discontinuance was seen. 12 subjects experienced at least one TRAE, and in all but one subject, these were low grade. One subject experienced a treatment-related immune system disorder. serious adverse events, all unrelated to treatment. TREM2 expression in archival tumor ranged from 0.0-20%. PY314 pharmacokinetics were linear, dose proportional, unaffected by concomitant pembrolizumab and with a half-life of 8-9 days. Best radiographic response was stable disease seen in 11 subjects (39.3%) ranging in duration from 9-42 weeks. 6 subjects with stable disease have progressed and 5 remain on treatment. Conclusions: PY314 was well tolerated and has an excellent safety profile both as a single agent and in combination with pembrolizumab. A recommended dose for expansion was derived and enrollment in five prespecified cancers is ongoing. Clinical trial information: 04691375.