COLUMBIA-1: a randomised study of durvalumab plus oleclumab in combination with chemotherapy and bevacizumab in metastatic microsatellite-stable colorectal cancer.

BACKGROUND: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC). METHODS: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy. RESULTS: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm. CONCLUSION: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC. REGISTRATION: NCT04068610.

Associations between context and affect within the daily lives of cancer caregivers.

PURPOSE: This study used ecological momentary assessment (EMA) to test the association between activity, location, and social company contexts with cancer caregivers' in-the-moment affect to identify precisely when and where to deliver psychological interventions for caregivers. METHODS: Current cancer caregivers (N = 25) received 8 EMA prompts per day for 7 consecutive days. At each prompt, caregivers reported their current positive affect and negative affect, as well as what they were doing, where they were located, and who they were with. Multilevel logistic regressions tested the associations between caregivers' contexts with their own person-mean-centered state (concurrent momentary level) and trait (overall weekly average) positive or negative affect. RESULTS: Caregivers reported lower state negative affect, as well as higher state positive affect, when socializing (ps < .001), when at a public location (ps < .03), and when around their friends, family, spouse/partner, or care recipient (i.e., person with cancer, ps < .02), relative to when not endorsing the context. Caregivers also reported lower state negative affect when eating/drinking or engaging in leisure (ps < .01; but no parallel effects for state positive affect). Caregivers reported higher state negative affect while working, when at their workplace, or when around work colleagues (ps < .001) and lower state positive affect when at home or alone (ps < .03). CONCLUSIONS: Results suggest the pertinence of a behavioral activation framework to mitigate the emotional strain of caregiving. Interventions that facilitate caregivers' ability to socialize with a range of friends and family, including their loved one with cancer, outside of the home may have the strongest positive emotional impact.

Phase II Single-Arm Study of Palbociclib and Cetuximab Rechallenge in Patients with KRAS/NRAS/BRAF Wild-Type Colorectal Cancer.

BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).

Feasibility of ecological momentary assessment to study depressive symptoms among cancer caregivers.

OBJECTIVE: Ecological momentary assessment (EMA) may help with the development of more targeted interventions for caregivers' depression, yet the use of this method has been limited among cancer caregivers. This study aimed to demonstrate the feasibility of EMA among cancer caregivers and the use of EMA data to understand affective correlates of caregiver depressive symptoms. METHODS: Caregivers (N = 25) completed a depressive symptom assessment (Patient Health Questionnaire-8) and then received eight EMA survey prompts per day for 7 days. EMA surveys assessed affect on the orthogonal dimensions of valence and arousal. Participants completed feedback surveys regarding the EMA protocol at the conclusion of the week-long study. RESULTS: Of 32 caregivers approached, 25 enrolled and participated (78%), which exceeded the a priori feasibility cutoff of 55%. The prompt completion rate (59%, or 762 of 1,286 issued) did not exceed the a priori cutoff of 65%, although completion was not related to caregivers' age, employment status, physical health quality of life, caregiving stress, or depressive symptoms or the patients' care needs (ps > 0.22). Caregivers' feedback about their study experience was generally positive. Mixed-effects location scale modeling showed caregivers' higher depressive symptoms were related to overall higher reported negative affect and lower positive affect, but not to affective variability. CONCLUSIONS: Findings from this feasibility study refute potential concerns that an EMA design is too burdensome for distressed caregivers. Clinically, findings suggest the potential importance of not only strategies to reduce overall levels of negative affect, but also to increase opportunities for positive affect.

Implementation of an Enhanced Recovery Protocol Is Associated With On-Time Initiation of Adjuvant Chemotherapy in Colorectal Cancer.

BACKGROUND: Delayed initiation of adjuvant chemotherapy negatively impacts long-term survival in patients with colorectal cancer. Colorectal enhanced recovery protocols result in decreased complications and length of stay; however, the impact of enhanced recovery on the timing of adjuvant chemotherapy remains unknown. OBJECTIVE: This study aimed to identify factors associated with on-time delivery of adjuvant chemotherapy after colorectal cancer surgery, hypothesizing that implementation of an enhanced recovery protocol would result in more patients receiving on-time chemotherapy. DESIGN: This was a retrospective cohort study comparing the rate of on-time adjuvant chemotherapy delivery after colorectal cancer resection before and after implementation of an enhanced recovery protocol. SETTINGS: The study was conducted at a large academic medical center. PATIENTS: All of the patients who underwent nonemergent colorectal cancer resections for curative intent from January 2010 to June 2017, excluding patients who had no indication for adjuvant chemotherapy, had received preoperative systemic chemotherapy, or did not have medical oncology records available were included. MAIN OUTCOME MEASURES: Patients before and enhanced recovery were compared, with the rate of on-time adjuvant chemotherapy delivery as the primary outcome. Adjuvant chemotherapy delivery was considered on time if initiated ≤8 weeks postoperatively, and treatment was considered delayed or omitted if initiated >8 weeks postoperatively (delayed) or never received (omitted). Multivariable logistic regression identified predictors of on-time chemotherapy delivery. RESULTS: A total of 363 patients met inclusion criteria, with 189 patients (52.1%) undergoing surgery after enhanced recovery implementation. Groups differed in laparoscopic approach and median procedure duration, both of which were higher after enhanced recovery. Significantly more patients received on-time chemotherapy after enhanced recovery implementation (p = 0.007). Enhanced recovery was an independent predictor of on-time adjuvant chemotherapy (p = 0.014). LIMITATIONS: The study was limited by its retrospective and nonrandomized before-and-after design. CONCLUSIONS: Enhanced recovery was associated with receiving on-time adjuvant chemotherapy. As prompt initiation of adjuvant chemotherapy improves survival in colorectal cancer, future investigation of long-term oncologic outcomes is necessary to evaluate the potential impact of enhanced recovery on survival. See Video Abstract at http://links.lww.com/DCR/B21. LA IMPLEMENTACIÓN DE UN PROTOCOLO DE RECUPERACIÓN ACELERADA SE ASOCIA CON EL INICIO A TIEMPO DE QUIMIOTERAPIA ADYUVANTE EN CÁNCER COLORRECTAL:: El inicio tardío de la quimioterapia adyuvante afecta negativamente la supervivencia a largo plazo en pacientes con cáncer colorrectal. Los protocolos de recuperación acelerada colorrectales dan lugar a una disminución de las complicaciones y la duración de estancia hospitalaria; sin embargo, el impacto de la recuperación acelerada en el momento de inicio de quimioterapia adyuvante sigue siendo desconocido.Este estudio tuvo como objetivo identificar los factores asociados con la administración a tiempo de la quimioterapia adyuvante después de la cirugía de cáncer colorrectal, con la hipótesis de que la implementación de un protocolo de recuperación acelerada daría lugar a que más pacientes reciban quimioterapia a tiempo.Estudio de cohorte retrospectivo que compara la tasa de administración de quimioterapia adyuvante a tiempo después de la resección del cáncer colorrectal antes y después de la implementación de un protocolo de recuperación acelerada.Centro médico académico grande.Todos los pacientes que se sometieron a resecciones de cáncer colorrectal no emergentes con intención curativa desde enero de 2010 hasta junio de 2017, excluyendo a los pacientes que no tenían indicación de quimioterapia adyuvante, que recibieron quimioterapia sistémica preoperatoria o no tenían registros médicos de oncología disponibles.Los pacientes se compararon antes y después de la implementación de la recuperación acelerada, con la tasa de administración de quimioterapia adyuvante a tiempo como el resultado primario. La administración de quimioterapia adyuvante se consideró a tiempo si se inició ≤8 semanas después de la operación, y el tratamiento se consideró retrasado / omitido si se inició> 8 semanas después de la operación (retrasado) o nunca fue recibido (omitido). La regresión logística multivariable identificó predictores de administración de quimioterapia a tiempo.363 pacientes cumplieron con los criterios de inclusión, con 189 (52.1%) pacientes sometidos a cirugía después de la implementación de recuperación acelerada. Los grupos difirieron en el abordaje laparoscópico y la duración media del procedimiento; ambos factores fueron mayores después de la recuperación acelerada. Significativamente más pacientes recibieron quimioterapia a tiempo después de la implementación de recuperación acelerada (p = 0.007). La recuperación acelerada fue un factor predictivo independiente de quimioterapia adyuvante a tiempo (p = 0.014).Diseño retrospectivo, tipo ¨antes y después¨ no aleatorizado.La recuperación acelerada se asoció con la recepción de quimioterapia adyuvante a tiempo. Debido a que el inicio rápido de la quimioterapia adyuvante mejora la supervivencia en el cáncer colorrectal, en el futuro será necesario investigar los resultados oncológicos a largo plazo para evaluar el impacto potencial de la recuperación acelerada en la supervivencia. Vea el Resumen en Video en http://links.lww.com/DCR/B21.

Integrating Storytelling into a Communication Skills Teaching Program for Medical Oncology Fellows.

Oncology training focuses primarily on biomedical content rather than psychosocial content, which is not surprising in light of the enormous volume of technical information that oncology fellows assimilate in a short time. Nonetheless, the human connection, and specifically communication skills, remains as important as ever in caring for highly vulnerable patients with cancer. We previously described a year-long communication skills curriculum for oncology fellows that consisted of monthly 1-hour seminars with role play as the predominant teaching method (Epner and Baile, Acad Med. 89:578-84, 2014). Over several years, we adapted the curriculum based on learner feedback and reflection by faculty and teaching assistants and consolidated sessions into quarterly 3-4-hour workshops. We now describe integrating stories into the curriculum as a way of building empathy and warming fellows to the arduous task of dealing with highly emotional content, such as conversations with young patients about transitioning off disease-directed therapy. Learners read and discussed published, medically themed stories; discussed their own patient care stories; and completed brief writing reflections and discussions. They then worked in small groups facilitated by faculty and upper level fellows who functioned as teaching assistants to work on applying specific skills and strategies to scenarios that they chose. Fellows completed anonymous surveys on which they rated the curriculum highly for relevance, value, organization, content, and teaching methods, including storytelling aspects. We conclude that sharing stories can help highly technical learners build reflective ability, mindfulness, and empathy, which are all critical ingredients of the art of medicine.

PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti-PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. EXPERIMENTAL DESIGN: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. RESULTS: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. CONCLUSIONS: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti-PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474.

A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. PATIENTS AND METHODS: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab's RP2D was 3,000 mg. During expansion, grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50-1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Complete response to immunotherapy in a patient with high-risk stage III colorectal cancer after ctDNA-guided detection of early adjuvant treatment failure.

The standard of care for stage III colorectal cancer (CRC) is curative resection with adjuvant chemotherapy (ACT). There is a high risk of recurrence particularly for high-risk patients with stage III disease, making close disease monitoring vital. Circulating tumor DNA (ctDNA) is now established as an effective method of early detection of disease relapse as well as postoperative risk stratification. However there remains a lack of established protocol for using ctDNA to assess response to ACT and in using that data to alter therapy in real time. A case is described of a patient with high-risk stage III CRC in whom failure of ACT was detected early and therapy was quickly changed based on rising ctDNA levels. The described patient had complete radiologic and clinical response to checkpoint inhibitor immunotherapy and remains free of disease after 18 months. This case demonstrates a promising example of how ctDNA can be used to both assess effectiveness of ongoing therapy and drive real-time change in treatment while sparing unnecessary chemotherapy toxicities.

Multi-omic analysis in normal colon organoids highlights MSH4 as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability.

INTRODUCTION: Lynch syndrome (LS) is a hereditary condition that increases the risk of colorectal (CRC) and extracolonic cancers that exhibit microsatellite instability (MSI-H). MSI-H is driven by defective mismatch repair (dMMR), and approximately 15% of nonhereditary CRCs also exhibit MSI-H. Here, we aimed to better define mechanisms underlying tumor initiation in LS and MSI-H cancers through multi-omic analyses of LS normal colon organoids and MSI-H tumors. METHODS: Right (n = 35) and left (n = 23) colon organoids generated from normal colon biopsies at routine colonoscopy of LS and healthy individuals were subjected to Illumina EPIC array. Differentially methylated region (DMR) analysis was performed by DMRcate. RNA-sequencing (n = 16) and bisulfite-sequencing (n = 15) were performed on a subset of right colon organoids. CRISPR-cas9-mediated editing of MMR genes in colon organoids of healthy individuals was followed by quantitative PCR of MSH4. The relationship between MSH4 expression and tumor mutational burden was further explored in three independent tumor data sets. RESULTS: We identified a hypermethylated region of MSH4 in both the right and left colon organoids of LS versus healthy controls, which we validated using bisulfite-sequencing. DMR analysis in three gastrointestinal and one endometrial data set revealed that this region was also hypermethylated in MSI-H versus microsatellite stable (MSS) tumors. MSH4 expression was increased in colon organoids of LS versus healthy subjects and in publicly available MSI-H versus MSS tumors across four RNA-seq and four microarray data sets. CRISPR-cas9 editing of MLH1 and MSH2, but not MSH6, in normal colon organoids significantly increased MSH4 expression. MSH4 expression was significantly associated with tumor mutational burden in three publicly available data sets. CONCLUSIONS: Our findings implicate DNA methylation and gene expression differences of MSH4 as a marker of dMMR and as a potential novel biomarker of LS. Our study of LS colon organoids supports the hypothesis that dMMR exists in the colons of LS subjects prior to CRC.

Mobile sensing to advance tumor modeling in cancer patients: A conceptual framework.

As mobile and wearable devices continue to grow in popularity, there is strong yet unrealized potential to harness people's mobile sensing data to improve our understanding of their cellular and biologically-based diseases. Breakthrough technical innovations in tumor modeling, such as the three dimensional tumor microenvironment system (TMES), allow researchers to study the behavior of tumor cells in a controlled environment that closely mimics the human body. Although patients' health behaviors are known to impact their tumor growth through circulating hormones (cortisol, melatonin), capturing this process is a challenge to rendering realistic tumor models in the TMES or similar tumor modeling systems. The goal of this paper is to propose a conceptual framework that unifies researchers from digital health, data science, oncology, and cellular signaling, in a common cause to improve cancer patients' treatment outcomes through mobile sensing. In support of our framework, existing studies indicate that it is feasible to use people's mobile sensing data to approximate their underlying hormone levels. Further, it was found that when cortisol is cycled through the TMES based on actual patients' cortisol levels, there is a significant increase in pancreatic tumor cell growth compared to when cortisol levels are at normal healthy levels. Taken together, findings from these studies indicate that continuous monitoring of people's hormone levels through mobile sensing may improve experimentation in the TMES, by informing how hormones should be introduced. We hope our framework inspires digital health researchers in the psychosocial sciences to consider how their expertise can be applied to advancing outcomes across levels of inquiry, from behavioral to cellular.

Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC. METHODS: Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination. RESULTS: Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2-141.8) and 37.9 (IQR: 22.9-173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively. CONCLUSIONS: Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.

Stoichiometry of STAT3 and mitochondrial proteins: Implications for the regulation of oxidative phosphorylation by protein-protein interactions.

The signal transducer and activator of transcription 3 (STAT3) is a transcription factor and downstream product of cytokine and growth factor pathways. Among members of the STAT family, STAT3 has garnered particular interest due to its role in cancer and development. Recently, it was proposed that STAT3 regulates cardiac ATP generation in vivo through protein interaction with the mitochondrial complexes of oxidative phosphorylation, specifically Complexes I/II. For this mechanism to work effectively, the cellular ratio of Complexes I/II and STAT3 must approach one. However, using three different proteomic approaches in cardiac tissue, we determined the ratio of Complexes I/II and STAT3 to be approximately 10(5). This finding suggests that direct protein interaction between Complexes I/II and STAT3 cannot be required for optimal ATP production, nor can it dramatically modulate oxidative phosphorylation in vivo. Thus, STAT3 is likely altering mitochondrial function via transcriptional regulation or indirect signaling pathways that warrant further investigation.

Using Graph Representation Learning to Predict Salivary Cortisol Levels in Pancreatic Cancer Patients.

Cortisol is a glucocorticoid hormone that is critical to immune system functioning. Studies show that prolonged exposure to high levels of cortisol can lead to a range of physical health ailments including the progression of tumor growth. The ability to monitor cortisol levels over time can therefore be used to facilitate decision-making during cancer treatment. However, collecting serum or saliva samples to monitor cortisol in situ is inconvenient, costly, and impractical. In this paper, we propose a general predictive modeling process that uses passively sensed actigraphy data to predict underlying salivary cortisol levels using graph representation learning. We compare machine learning models with handcrafted feature engineering and with graph representation learning, which includes Graph2Vec, FeatherGraph, GeoScattering and NetLSD. Our preliminary results generated from data from 10 newly diagnosed pancreatic cancer patients demonstrate that machine learning models with graph representation learning can outperform the handcrafted feature engineering to predict salivary cortisol levels.

TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma.

Tumors that lack pre-existing immune infiltration respond poorly to T cell checkpoint blockade immunotherapy. These cancers often surround themselves with high densities of suppressive myeloid stroma while excluding immunostimulatory dendritic cells. Tumor-resident myeloid cells and selected lymphocyte populations retain expression of Toll-like Receptors (TLR) that sense common features of pathogens and activate innate immunity in response. We explored whether agonists of TLR9 could augment innate immunity to promote tumor regression alone or in combination with T cell checkpoint blockade. In the setting of the immunogenic B16-Ova (Ovalbumin) expressing melanoma model, local injection of the CpG oligonucleotide TLR9 agonist ODN1826 combined with systemic CTLA-4 blockade cured 45% of mice of both their treated and an untreated tumor on the opposite flank demonstrating the synergistic potential of this combination. Next, in the non-immunogenic B16-F10 melanoma model, we showed that only intra-tumoral, but not systemic TLR9 activation augments the therapeutic potential of checkpoint blockade. In this setting, intra-tumoral TLR9 activation cooperated equally with either CTLA-4 or PD-1 blockade co-administered locally or given systemically; however, the uninjected tumor rarely regressed. Anti-CTLA-4 combinations were associated with improved intra-tumoral CD8 to regulatory T cell ratios, while anti-PD-1 combinations elicited improved ratios of CD8 T cells relative to suppressive myeloid stroma. Using both a TLR9 agonist (MGN1703) and a CTLA-4 antibody (9D9-IgG2a) of increased potency cured 50% of bi-lateral B16-F10 melanoma. These findings suggest that intra-tumoral TLR9 agonists can improve sensitivity of poorly immunogenic tumors to T cell checkpoint blockade, and that newer, higher potency TLR agonists and checkpoint antibodies can raise the therapeutic ceiling for this combination therapy.

Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.

Purpose: Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist-driven tumor immunity from hepatotoxicity.Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without coadministration of checkpoint blockade, via (i) measurement of serum transaminase levels, (ii) imaging of liver immune infiltrates, and (iii) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines, and chemokines.Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Coadministration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma.Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Coadministration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity. Clin Cancer Res; 24(5); 1138-51. ©2018 AACR.

STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial.

BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL. METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

Revascularization strategies and in-hospital management in acute coronary syndromes complicated by hemophilia A or hemophilia B.

: Among adult patients with hemophilia A and hemophilia B the emergent management of acute coronary syndromes (ACSs) is challenging, and exposure to antithrombotic agents and/or revascularization procedures may confer an enhanced risk of bleeding. We sought to identify clinical characteristics and in-hospital outcomes among ACS patients with hemophilia A/hemophilia B, compared with matched noncoagulopathic ACS controls. Case discharges from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality (1998-2011) had International Classification of Diseases, 9th Revision codes for hemophilia A/hemophilia B and ACS. Control discharges were matched to cases by year of discharge and hospital. Discharges in both groups were assessed for cardiovascular risk factors, type of ACS, use of coronary artery bypass grafting, percutaneous coronary intervention (PCI), bare-metal stent and/or drug-eluting stent, bleeding, and death. In total, 237 cases and 148 848 matched controls were identified. Among cases, HIV/Hepatitis C positivity was more common and obesity/hyperlipidemia less common. ST-elevation myocardial infarction (STEMI) occurred less frequently among hemophilia A cases than controls. hemophilia A and hemophilia B cases were more likely to be managed medically. Cases treated with coronary stent placement were more likely to receive a bare-metal stent than controls. Among PCI, bleeding was more common among hemophilia A cases. The death rates were comparable between groups. ACS-hemophilia A/hemophilia B cases were more often treated noninvasively compared with controls, suggesting an avoidance of PCI/coronary artery bypass grafting in this population, and bleeding (among hemophilia A) was more common. These findings support further study of the management of ACS and in-hospital outcomes among individuals with hemophilia.

Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity.

Coordinated manipulation of independent immune regulatory pathways in the tumor microenvironment-including blockade of T-cell checkpoint receptors and reversal of suppressive myeloid programs-can render aggressive cancers susceptible to immune rejection. Elevated toxicity associated with combination immunotherapy, however, prevents translation of the most efficacious regimens. We evaluated T-cell checkpoint-modulating antibodies targeting CTLA-4, PD-1, and 4-1BB together with myeloid agonists targeting either STING or Flt3 in the TRAMP-C2 model of prostate cancer to determine whether low-dose intratumoral delivery of these agents could elicit systemic control of multifocal disease. Intratumoral administration of the STING agonist cyclic di-GMP (CDG) or Flt3 Ligand (Flt3L) augmented the therapeutic effect of systemic triple checkpoint modulation and promoted the cure of 75% of mice with bilateral TRAMP-C2; however, when all agents were administered locally, only CDG mobilized abscopal immunity. Combination efficacy correlated with globally enhanced ratios of CD8+ T cells to regulatory T cells (Treg), macrophages, and myeloid-derived suppressor cells, and downregulation of the M2 marker CD206 on tumor-associated macrophages. Flt3L improved CD8+ T-cell and dendritic cell infiltration of tumors, but was diminished in efficacy by concomitant Treg expansion. Although intratumoral CDG/checkpoint therapy invokes substantial ulceration at the injection site, reduced CDG dosing can preserve tissue integrity without sacrificing therapeutic benefit. For high-order combinations of T-cell checkpoint antibodies and local myeloid agonists, systemic antibody administration provides the greatest efficacy; however, local administration of CDG and antibody provides substantial systemic benefit while minimizing the potential for immune-related adverse events. Cancer Immunol Res; 5(8); 676-84. ©2017 AACR.

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies.

BACKGROUND: Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. METHODS: Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response. RESULTS: The primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2-related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type. CONCLUSIONS: Our findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated. TRIAL REGISTRATION: Clinicaltrials.gov NCT01738139, registered 28 November 2012.