Ramesh Rengan

Bio: Ramesh Rengan is an academic researcher from University of Washington. The author has contributed to research in topics: Radiation therapy & Lung cancer. The author has an hindex of 20, co-authored 89 publications receiving 2778 citations. Previous affiliations of Ramesh Rengan include University of Washington Medical Center & University of Pennsylvania.

Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer

Abstract: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

A moving target: Image guidance for stereotactic body radiation therapy for early-stage non-small cell lung cancer

Abstract: Purpose Precise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion. Methods and Materials Eighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion. Results The mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function. Conclusions Kilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.

Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer.

Abstract: Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions.

Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study.

Abstract: Background Bones are one of the most common metastatic sites for solid malignancies. Bone metastases can significantly increase mortality and decrease the quality of life of cancer patients. In the United States, around 350,000 people die each year from bone metastases. This study aimed to analyze and update the incidence and prognosis of bone metastases with solid tumors at the time of cancer diagnosis and its incidence rate for each solid cancer. Methods We used the Surveillance, Epidemiology, and End Results (SEER) database to find patients diagnosed with solid cancers originating from outside the bones and joints between 2010 and 2016. Data were stratified by age, sex, and race. Patients with a tumor in situ or with an unknown bone metastases stage were excluded. We then selected most of the sites where cancer often occurred, leaving 2,207,796 patients for the final incidence analysis. For the survival analysis, patients were excluded if they were diagnosed at their autopsy or on their death certificate, or had unknown follow-ups. The incidence of bone metastases and overall survival was compared between patients with different primary tumor sites. Results We identified 2,470,634 patients, including 426,594 patients with metastatic disease and 113,317 patients with bone metastases, for incidence analysis. The incidence of bone metastases among the metastatic subset was 88.74% in prostate cancer, 53.71% in breast cancer, and 38.65% in renal cancer. In descending order of incidence, there were patients with other cancers in the genitourinary system (except for renal, bladder, prostate, and testicular cancer) (37.91%), adenocarcinoma of the lung (ADC) (36.86%), other gynecologic cancers (36.02%), small-cell lung cancer (SCLC) (34.56%), non-small cell lung cancer not otherwise specified and others [NSCLC (NOS/others)] (33.55%), and bladder (31.08%) cancers. The rate of bone metastases is 23.19% in SCLC, 22.50% in NSCLC (NOS/others), 20.28% in ADC, 8.44% in squamous cell carcinoma of the lung (SCC), and 4.11% in bronchioloalveolar carcinoma [NSCLC (BAC)]. As for the digestive system, the overall bone metastases rate was 7.99% in the esophagus, 4.47% in the gastric cancer, 4.42% in the hepatobiliary cancer, 3.80% in the pancreas, 3.26% in other digestive organs, 1.24% in the colorectum, and 1.00% in the anus. Overall, the incidence rate of bone metastases among the entire cohort in breast and prostate cancer was 3.73% and 5.69%, respectively. Conclusions The results of this study provide population-based estimates for the incidence rates of patients with bone metastases at initial diagnosis of their solid tumor. The findings can help clinicians to early detect bone metastases by bone screening to anticipate the occurrence of symptoms and favorably improve the prognosis.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

Abstract: Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

Abstract: With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.

Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Abstract: Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.

A guide to cancer immunotherapy: from T cell basic science to clinical practice.

Abstract: The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.