Response to Nivolumab and Ipilimumab in Microsatellite Instability-High (MSI-H) Cervical Carcinoma with Acquired Resistance to Pembrolizumab: A Case Report and Literature Review.

As the use of immune checkpoint inhibitors (ICIs) in treating a variety of cancer types has increased in recent years, so too have the number of reports on patients acquiring resistance to these therapies. Overcoming acquired resistance to immunotherapy remains an important need in the field of immuno-oncology. Herein, we present a case that suggests sequential administration of combination immunotherapy may be beneficial to advanced cervical cancer patients exhibiting acquired resistance to mono-immunotherapy. The patient's tumor is microsatellite instability-high (MSI-H), which is an important biomarker in predicting ICI response. Results from recent interim prospective studies using combination immunotherapy (eg, nivolumab and ipilimumab) with anti-PD-1 plus anti-CTLA-4 inhibitor following progression on anti-PD-1 inhibitors (eg, nivolumab) have shown anti-tumor activity in patients with advanced melanoma and metastatic urothelial carcinoma. We also introduce retrospective studies and case reports/case series of dual checkpoint inhibition with anti-PD-1 inhibitor plus anti-CTLA-4 inhibitor after progression on prior anti-PD/PD-L1 monotherapy. To date, there has been no prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 therapy in patients with MSI-H tumors or advanced cervical cancer. In this report, we provide evidence that supports future investigations into such treatments.

Artificial Intelligence-based Radiomics in the Era of Immuno-oncology.

The recent, rapid advances in immuno-oncology have revolutionized cancer treatment and spurred further research into tumor biology. Yet, cancer patients respond variably to immunotherapy despite mounting evidence to support its efficacy. Current methods for predicting immunotherapy response are unreliable, as these tests cannot fully account for tumor heterogeneity and microenvironment. An improved method for predicting response to immunotherapy is needed. Recent studies have proposed radiomics-the process of converting medical images into quantitative data (features) that can be processed using machine learning algorithms to identify complex patterns and trends-for predicting response to immunotherapy. Because patients undergo numerous imaging procedures throughout the course of the disease, there exists a wealth of radiological imaging data available for training radiomics models. And because radiomic features reflect cancer biology, such as tumor heterogeneity and microenvironment, these models have enormous potential to predict immunotherapy response more accurately than current methods. Models trained on preexisting biomarkers and/or clinical outcomes have demonstrated potential to improve patient stratification and treatment outcomes. In this review, we discuss current applications of radiomics in oncology, followed by a discussion on recent studies that use radiomics to predict immunotherapy response and toxicity.

Association of HLA class I homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer treated with chemo-immunotherapy or immunotherapy as first-line therapy.

BACKGROUND: Homozygosity at HLA-I locus has been reported to be an unfavorable predictive biomarker of second-line or beyond immunotherapy in patients with different types of cancer. The linkage between HLA-I zygosity and survival in NSCLC patients treated with first-line immunotherapy with or without chemotherapy has not been reported. METHODS: Next generation sequencing with HLA genotyping was performed on patients with advanced NSCLC treated with immune checkpoint inhibitors with or without chemotherapy as first-line (N = 29). Progression free survival was compared between HLA-I homozygous (defined as homozygosity in at least one locus A, B, or C) and heterozygous patients. Kaplan-Meier curves were built, and log-rank test was used. RESULTS: Among 29 enrollees, 25 patients (86.2%) were HLA-I heterozygous and four patients (13.8%) were HLA-I homozygous. Treatment response was not available in five patients with HLA-I heterozygosity. Among 20 patients with HLA-I heterozygosity, five patients (20.0%) had partial response, 10 patients (50.0%) had stable disease, two patients (8.0%) had non-complete response/non-progressive disease, and three patients (12.0%) had progressive disease. Among four patients with HLA-I heterozygosity, one patient (25.0%) had partial response, one patient (25.0%) had stable disease, and two patients (50.0%) had progressive disease. The median progression free survival was not reached in heterozygous group and was 2.97 months in homozygous group (Log-rank p = 0.68). CONCLUSIONS: We observed a trend toward an inverse association between HLA-I homozygosity and survival outcomes in patients with NSCLC treated with first-line therapy in conjunction with immunotherapy. Further prospective studies to validate aforementioned relationship are warranted.

Blood transfusions may adversely affect survival outcomes of patients with lung cancer: a systematic review and meta-analysis.

BACKGROUND: Despite common use in clinical practice, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. The purpose of the current study is to perform an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients. METHODS: We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to November 2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I2 test. Publication bias was explored via funnel plot and trim-and-fill analyses. RESULTS: We included 23 cohort studies with 12,175 patients (3,027 cases and 9,148 controls) for meta-analysis. Among these records, 22 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.35, 95% CI: 1.14-1.61, P<0.001, I2=0%) and DFS (HR=1.46, 95% CI: 1.15-1.86, P=0.001, I2=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI: 1.07-1.49, P=0.006; DFS: HR=1.35, 95% CI: 1.08-1.69, P=0.008). CONCLUSIONS: Blood transfusions were associated with decreased survival of patients with lung cancer.

Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC).

Metformin has been widely used as the treatment of type II diabetes mellitus for its anti-hyperglycemic effect. In recent years, it has also been extensively studied for its anti-cancer effect as it diminishes immune exhaustion of CD8 + tumor-infiltrating lymphocytes (TILs). It decreases apoptosis of CD8 + TILs, thereby enhancing T cell-mediated immune response to tumor cells. Here, we present a unique case of a patient with small cell lung cancer (SCLC) who exhibited an overall partial response as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) since starting metformin in combination with nivolumab therapy. Our patient had been treated with nivolumab monotherapy for 2 years until she had progression of disease. After she was started on metformin along with nivolumab therapy, she has shown a significant durable response for over 6 months. Many patients develop resistance to immunotherapy such as antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Tumor hypoxia is one of the resistance factors. Signals activated by hypoxic environments in tumors are associated with decreased sensitivity to the PD-1 blockade. Metformin inhibits oxygen consumption in tumor cells in vitro and in vivo, reducing intratumoral hypoxia. These data suggest that metformin can improve susceptibility to anti-PD-1 treatment. To the best of our knowledge, our case is the first reported example demonstrating a proof-of-concept that metformin can contribute to overcoming acquired resistance to PD-1 inhibitors.