Role of Immunotherapy in Gastroesophageal Cancers-Advances, Challenges and Future Strategies.

BACKGROUND: Gastroesophageal cancers (GECs) carry considerable morbidity and mortality, and demonstrate geographical histological variances in addition to molecular heterogeneity. Consequently, the immunogenicity of the different subtypes, which can predict the likelihood of immunotherapy response, can vary. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of many cancer types over the past decade but has been slower to gain a foothold in the treatment paradigm of GECs. METHODS: This article reviews the existing evidence and use approvals for immunotherapies and immune-based treatments in GECs, in the neoadjuvant, adjuvant and metastatic disease settings. The challenges of and limitations to ICI application in current clinical practice are examined. Ongoing clinical trials and future directions of research are also considered. CONCLUSION: ICI therapy has become an established treatment option within GECs, both perioperatively and in advanced disease. However, nuances in terms of its use are not yet fully understood. Ongoing research proposes to broaden the application of immunotherapies in GECs with the potential to continue to improve outcomes.

Brave new world-new and emerging treatments for gastric cancer.

Despite considerable international heterogeneity in the incidence and histological subtypes of gastric cancer (GC), in addition to more recent epidemiological trends, chemotherapy has long represented the main systemic therapeutic option in its treatment. For the roughly 20% of GC with human epidermal growth factor receptor 2 (HER2) overexpression, there is a more recently established role for the addition of HER2+ based therapy in the form of trastuzumab. However, while immune checkpoint inhibitors (ICIs) have revolutionised the treatment of other malignancies including melanoma and renal cell carcinoma over the past decade, they have only gained a foothold in GC in more recent years. This article reviews the existing evidence for ICIs in GC as a novel therapeutic option. It also looks to ongoing trials of immune checkpoint inhibition both in the perioperative and advanced setting, and in combination with other therapeutic targets including HER2+. Other investigational immune based therapies including chimeric antigen receptor T-cell (CAR-T) therapy and anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (anti-TIGIT) therapy are considered, in addition to reviewing the building evidence for alternative therapeutic targets currently under investigation in GC, including fibroblast growth factor receptor 2b (FGFR2b) and claudin 18.2 amongst others. These novel and evolving targets represent a brave new world in therapeutic intervention in GC, with the potential to transform outcomes for patients internationally.

Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer.

BACKGROUND: Oncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial. METHODS: Adult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring. RESULTS: Thirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment. CONCLUSION: PexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers. TRIAL REGISTRATION NUMBER: NCT03206073.

Immune Checkpoint Inhibitors: Changing the Treatment Landscape in Esophagogastric Adenocarcinoma.

In the West, recent decades have demonstrated an epidemiological trend towards esophago-gastric adenocarcinomas (EGAC), with considerable associated mortality. Historically, chemotherapy has represented the sole systemic treatment option in the advanced EGAC setting, in addition to complementing the role of surgery and radiotherapy in the case of localized disease. Immune checkpoint inhibitors (ICIs) represent a novel systemic therapeutic choice and have revolutionized the management of other malignancies, including melanoma and renal cell carcinomas. This article considers the rationale for ICIs in EGAC, reviews the evidence supporting their role in the current standard of care in EGAC, and briefly considers ongoing trials and future directions for the ICI class in EGAC.

Targeting KRAS in Pancreatic Cancer.

Pancreatic cancer is mainly driven by mutations in the KRAS oncogene. While this cancer has shown remarkable therapy resistance, new approaches to inhibit mutated KRAS, KRAS activators and effectors show promise in breaking this therapeutic deadlock. Here, we review these innovations in therapies that target RAS signaling in pancreatic cancer from a clinical point of view. A number of promising approaches are currently in clinical trials or in clinical development. We focus on small-molecule drugs but also discuss immunotherapies and tumor vaccines.

Enhanced toxicity to chemoradiation in a patient with Anti-Jo-1-antisynthetase syndrome.

Appropriate counseling of patients with autoimmune connective tissue disorders (ACTDs) is often challenging for radiation oncologists, especially regarding anticipated side-effects of radiation treatment. These patients can have highly variable and unpredictable sequelae from radiation therapy, and the uncertainty builds when radiation is convoluted by the addition of concurrent chemotherapy. While many patients may experience a mild intensification of toxicity above what is expected, some patients experience much more severe toxicity. These patients become critical learning cases, enabling a better understanding of the delicate and complex ways in which radiation response is altered in the context of ACTDs while allowing other patients with similar ACTD profiles to benefit from past experience. Our report makes an important contribution to this space by describing a particularly severe case of toxicity that manifested in such a patient and the ensuing clinical decision-making. Comprehensive genotyping of classic pharmacokinetic and pharmacodynamic pathway genes (including mutations in DPD and CDA) did not reveal any signatures that might explain her enhanced toxicity and we demonstrate that severe toxicity can still manifest in the era of modern conformal radiation treatments for rectal cancer. We urge caution in the treatment of patients with rare ACTDs, but also emphasize that curative treatment should not be withheld in such patients. We conclude by advocating for the development and maintenance of a prospective multiinstitutional database of patients with ACTDs to help inform and improve future practice.

Multispecialty surgical management of large clavicular tumor: A case report.

INTRODUCTION: Primary and metastatic malignancies of the clavicle are extremely uncommon and difficult to treat. It carries a high morbidity rate. Total or partial claviculectomy is the recommended treatment option. PRESENTATION OF CASE: A 59-year-old male was admitted with a large left clavicular huge mass; biopsy showed poorly differentiated adenocarcinoma. Treatment started with chemoradiotherapy followed by complete excision of the tumor surgically. DISCUSSION: For treating this rare, difficult case, partial claviculectomy performed by a multispecialty team integrating three surgical skill sets: thoracic, ENT, and orthopedic surgeons, yields the best results. Clavicular carcinoma of known primary (CUP) is rare, and chemoradiotherapy showed preferable results in management. CONCLUSION: MDT reviews with surgeons, radiologists, pathologists, oncologists, and radiation oncologists are required in rare and complex cases of clavicular malignancy. Multispecialty surgical involvement is required for the safe excision of clavicular tumors with appropriate oncologic margins and fewer complications.

Liver Immunology, Immunotherapy, and Liver Cancers: Time for a Rethink?

The complex immune system of the liver has a major role in tumor surveillance, but also partly explains why current immune therapies are poorly effective against liver cancers. Known primarily for its tolerogenic capacity, the hepatic immune repertoire also comprises diverse populations of armored immune cells with tumor surveillant roles. In healthy people, these work together to successfully identify malignant cells and prevent their proliferation, thus halting tumor formation. When frontline hepatic immune surveillance systems fail, compromised hepatic immunity, driven by obesity, infection, or other pathological factors, allows primary or secondary liver cancers to develop. Tumor growth promotes the normal tolerogenic immunological milieu of the liver, perhaps explaining why current immunotherapies fail to work. This review explores the complex local liver immune system with the hope of identifying potential therapeutic targets needed to best overcome immunological barriers in the liver to create an environment no longer hostile to immunotherapy for the treatment of liver cancer.

A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma.

BACKGROUND: We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. PATIENTS AND METHODS: Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. RESULTS: Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. CONCLUSION: Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03111732).

Prioritising Informed Health Choices Key Concepts for those impacted by cancer: a protocol.

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.

Metastatic medullary thyroid carcinoma presenting as ectopic Cushing's syndrome.

SUMMARY: A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6-29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L (<50) and subsequently a low dose DST with a cortisol post 48 h of dexamethasone of 773 nmol/L (<50) and an elevated ACTH 98 ng/L. A corticotropin-releasing factor (CRF) test suggested ectopic ACTH secretion. The patient was commenced on teriparatide for osteoporosis and metyrapone to control the hypercortisolaemia. A positron emission tomography (PET) scan to look for the source of ACTH secretion demonstrated right neck adenopathy. Biopsy and subsequent lymph node dissection were performed and histology revealed a metastatic neuroendocrine tumour. Immunostaining was positive for calcitonin and thyroid transcription factor 1 (TTF1). Serum calcitonin was also significantly elevated at 45 264 ng/L (<10). The patient proceeded to a total thyroidectomy and left neck dissection. Histology confirmed a 7 mm medullary thyroid carcinoma (MTC). Post-operatively, the patient commenced vandetanib therapy and achieved a clinical and biochemical response. After approximately 18 months of vandetanib therapy, the patient developed recurrent disease in his neck. He is currently on LOXO-292 and is doing well 36 months post-diagnosis. LEARNING POINTS: Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess. MTC should be considered when searching for sources of ectopic ACTH secretion. Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.

A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype.

We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI-high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI-high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21-day cycle. A total of 6 patients with CHFR-methylated, MSI-high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression-free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof-of-concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker-selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.

Emerging RAS-directed therapies for cancer.

RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).

Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

PURPOSE: The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. PATIENTS AND METHODS: Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. RESULTS: Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2. CONCLUSIONS: The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

A Pilot Study of the PD-1 Targeting Agent AMP-224 Used With Low-Dose Cyclophosphamide and Stereotactic Body Radiation Therapy in Patients With Metastatic Colorectal Cancer.

BACKGROUND: The prognosis of metastatic colorectal cancer (mCRC) is poor. We assessed the feasibility, safety, and efficacy of the anti-programmed cell death 1 fusion protein AMP-224 in combination with low-dose cyclophosphamide and stereotactic body radiation (SBRT) treatment in patients with mCRC refractory to standard chemotherapy. PATIENTS AND METHODS: Fifteen patients were enrolled. Six received SBRT 8 Gy on day 0 (dose level 1), whereas 9 received 8 Gy on days -2 to day 0. All received cyclophosphamide 200 mg/m2 intravenously (I.V.) on day 0. On day 1, both groups received AMP-224 10 mg/kg I.V., repeated every 2 weeks for a total of 6 doses. Primary end points were feasibility and safety. RESULTS: Ten (67%) patients completed 6 doses of AMP-224; 5 patients (33%) discontinued treatment because of disease progression. No dose-limiting toxicity was observed; 9 patients (60%) experienced treatment-related adverse events, all Grade 1 or 2. No objective response was noted; 3 patients (20%) had stable disease. Median progression-free survival and overall survival were 2.8 months (95% confidence interval [CI], 1.2-2.8 months) and 6.0 months (95% CI, 2.8-9.6 months), respectively. M2 macrophage polarization was present in the pretreatment tumor biopsy samples, but not post-treatment samples. CONCLUSION: AMP-224 in combination with SBRT and low-dose cyclophosphamide was well tolerated, however, no significant clinical benefit was observed in patients with mCRC.

The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma.

BACKGROUND: Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%. METHODS: Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients. RESULTS: Tremelimumab therapy increased CD4+-HLA-DR+, CD4+PD-1+, CD8+HLA-DR+, CD8+PD-1+, CD4+ICOS+ and CD8+ICOS+ T cells in the peripheral blood of the treated patients. Patients with higher CD4+PD1+ cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3+ T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy. CONCLUSION: In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer.

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)ß screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.