Anish Thomas

Antibody-drug conjugates for cancer therapy

Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody-drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody-drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody-drug linker technology. Improved understanding of the mechanistic basis of antibody-drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy.

Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression

In patients with advanced chemotherapy-refractory mesothelioma, treatment with the anti-mesothelin immunotoxin SS1P and immunosuppression with pentostatin and cyclophosphamide resulted in marked and durable tumor regressions. Combating Mesothelioma by Suppressing Friendly Fire Immunotoxins, which combine a bacterial toxin with an antibody fragment that recognizes a specific protein, offer a way to selectively target and kill cancer cells. Unfortunately, the patient’s immune system usually attacks the immunotoxin as a foreign protein, destroying it before it can reach its target and deliver the toxin to the tumor. Now, Hassan and coauthors have demonstrated a combination treatment approach for preventing the formation of antitoxin antibodies in mesothelioma patients. Mesothelioma is an aggressive tumor of the pleural and peritoneal membranes, which normally has a poor prognosis and very limited treatment options. SS1P is an immunotoxin targeting mesothelin, a protein that is only found in the mesothelial membranes and highly expressed in mesothelioma. In past clinical trials, the vast majority of treated patients developed antibodies against SS1P after only one cycle of treatment, precluding its continued use as a therapeutic agent. To overcome this problem, Hassan et al. treated chemotherapy-resistant mesothelioma patients with pentostatin and cyclophosphamide, chemotherapeutic agents that specifically deplete lymphocytes and can therefore prevent the formation of antitoxin antibodies, before giving SS1P to the patients. This treatment combination greatly delayed antibody formation, allowing the patients to receive multiple cycles of SS1P, which resulted in improved clinical outcomes. Future work will be needed to further prolong the presence of this immunotoxin because most patients in the current trial eventually developed antibodies against SS1P. Additional work will also be necessary to clarify the mechanism of the combination treatment and determine whether the immunomodulatory drugs contribute any direct antitumor effects. Nevertheless, the results presented by Hassan and coauthors provide a promising approach for treating an aggressive and deadly tumor, and demonstrate a clever way to overcome immune rejection of immunotoxin treatment. Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy-refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed.

Refining the treatment of NSCLC according to histological and molecular subtypes

In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.

New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas.

Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.

A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical And Translational Study

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049). Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.

Mutations of epigenetic regulatory genes are common in thymic carcinomas

Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy.

Colonic Necrosis Due to Oral Kayexalate in a Critically-Ill Patient

Kayexalate (sodium polystyrene sulfonate in sorbitol) is commonly used for treatment of hyperkalemia. We describe the case of a critically ill patient who developed colonic necrosis after oral administration of kayexalate.

Expression of a novel tropomyosin isoform in axolotl heart and skeletal muscle

TPM1κ is an alternatively spliced isoform of the TPM1 gene whose specific role in cardiac development and disease is yet to be elucidated. Although mRNA studies have shown TPM1κ expression in axolotl heart and skeletal muscle, it has not been quantified. Also the presence of TPM1κ protein in axolotl heart and skeletal muscle has not been demonstrated. In this study, we quantified TPM1κ mRNA expression in axolotl heart and skeletal muscle. Using a newly developed TPM1κ specific antibody, we demonstrated the expression and incorporation of TPM1κ protein in myofibrils of axolotl heart and skeletal muscle. The results support the potential role of TPM1κ in myofibrillogenesis and sarcomeric function. J. Cell. Biochem. 110: 875–881, 2010.

Biomarkers in Early-Stage Non–Small-Cell Lung Cancer: Current Concepts and Future Directions

Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non–small-cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately, a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation, and protein signatures is being explored in patients with early-stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early-stage NSCLC.

18F-Fluorodeoxyglucose Positron Emission Tomography in the Management of Patients with Thymic Epithelial Tumors

Purpose: There are limited data regarding the role of 18F-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs. Experimental Design: [18F]-FDG PET/computed tomographic (CT) scans were conducted at baseline and after 6 weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. On the basis of data from other solid tumors, metabolic response was defined as a reduction of [18F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions. Results: Fifty-six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P < 0.0001–0.0003): sensitivity and specificity for prediction of best response were 95% and 100%, respectively. Metabolic responders had significantly longer progression-free survival (median, 11.5 vs. 4.6 months; P = 0.044) and a trend toward longer overall survival (median, 31.8 vs. 18.4 months; P = 0.14) than nonresponders. [18F]-FDG uptake was significantly higher in thymic carcinoma than in thymoma (P = 0.0004–0.0010). Conclusion: In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [18F]-FDG PET may be used to monitor treatment efficacy and assess histologic differences in patients with advanced TETs. Clin Cancer Res; 19(6); 1487–93. ©2013 AACR.