Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers.

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs by stratifying patients into immune-specific subtypes (immunotypes) to decipher the molecular and cellular presentations and signaling events of this heterogeneous disease and associating them with their clinical outcomes and potential treatment options. EXPERIMENTAL DESIGN: We profiled 730 immune genes in 88 retrospective Indian TNBC samples using the NanoString platform, established immunotypes using non-negative matrix factorization-based machine learning approach, and validated them using Western TNBCs (n=422; public datasets). Immunotype-specific gene signatures were associated with clinicopathological features, immune cell types, biological pathways, acute/chronic inflammatory responses, and immunogenic cell death processes. Responses to different immunotherapies associated with TNBC immunotypes were assessed using cross-cancer comparison to melanoma (n=504). Tumor-infiltrating lymphocytes (TILs) and pan-macrophage spatial marker expression were evaluated. RESULTS: We identified three robust transcriptome-based immunotypes in both Indian and Western TNBCs in similar proportions. Immunotype-1 tumors, mainly representing well-known claudin-low and immunomodulatory subgroups, harbored dense TIL infiltrates and T-helper-1 (Th1) response profiles associated with smaller tumors, pre-menopausal status, and a better prognosis. They displayed a cascade of events, including acute inflammation, damage-associated molecular patterns, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. On the other hand, immunotype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal immunotypes, and an intermediate prognosis. In contrast to the two T-cell enriched immunotypes, immunotype-3 patients expressed innate immune genes/proteins, including those representing myeloid infiltrations (validated by spatial immunohistochemistry), and had poor survival. Remarkably, a cross-cancer comparison analysis revealed the association of immunotype-1 with responses to anti-PD-L1 and MAGEA3 immunotherapies. CONCLUSION: Overall, the TNBC immunotypes identified in TNBCs reveal different prognoses, immune infiltrations, signaling, acute/chronic inflammation leading to immunogenic cell death of cancer cells, and potentially distinct responses to immunotherapies. The overlap in immune characteristics in Indian and Western TNBCs suggests similar efficiency of immunotherapy in both populations if strategies to select patients according to immunotypes can be further optimized and implemented

Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small-cell lung cancer: a multicenter, randomized, open-label Phase II study

K Govind Babu,1 Kumar Prabhash,2 Ashok K Vaid,3 Bhawna Sirohi,3 Ravi B Diwakar,4 Raghunadha Rao,5 Madhuchanda Kar,6 Hemant Malhotra,7 Shona Nag,8 Chanchal Goswami,9 Vinod Raina,10 Ravi Mohan111Kidwai Memorial Institute of Oncology, Bangalore, 2Tata Memorial Hospital, Mumbai, 3Artemis Health Institute, Delhi, 4Bangalore Institute of Oncology, Bangalore, 5Nizam Institute of Medical Sciences, Hyderabad, 6B R Singh Hospital, Kolkata, 7Birla Cancer Centre, Jaipur, 8Jehangir Hospital, Pune, 9B P Poddar Hospital and Medical Research Ltd, Kolkata, 10Institute Rotary Cancer Hospital, New Delhi, 11King George Hospital, Visakhapatnam, IndiaBackground: The purpose of this study was to evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in patients with stage IIIB/IV non-small-cell lung cancer.Methods: This multicenter, open-label, Phase II study randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab 200 mg was administered once weekly for 13 weeks during the first two phases with four cycles of chemotherapy and docetaxel 75 mg/m2 and carboplatin (area under the curve 5 mg/mL*min) every 3 weeks for a maximum of four cycles during the concomitant phase. The primary endpoint was objective response rate (sum of complete response and partial response). Secondary endpoints, ie, overall survival and progression-free survival, were estimated using the Kaplan–Meier method. Efficacy was evaluated on the intent-to-treat and efficacy-evaluable sets. Safety was assessed from adverse event and serious adverse event data.Results: The objective response rate was significantly higher in the nimotuzumab group than in the control group in the intent-to-treat population (54% versus 34.5%; P=0.04). A complete response and partial response were achieved in 3.6% and 50% of patients, respectively, in the nimotuzumab group, and in 4% and 30.9% of patients, respectively, in the control group. No significant differences in median progression-free survival and overall survival were observed. Safety profiles were comparable between the two groups.Conclusion: Nimotuzumab plus chemotherapy significantly improved the objective response rate as compared with chemotherapy alone. The combination was safe and well tolerated in patients with stage IIIB/IV non-small-cell lung cancer.Keywords: carboplatin, docetaxel, epidermal growth factor receptor, nimotuzumab, non-small cell lung cance

Supporting food security in the 21st century through resource-conserving increases in agricultural production

<p>Abstract</p> <p>The Green Revolution was accomplished under a set of demographic, economic, climatic and other conditions in the 20th century that have been changing and will surely be different and more difficult in the decades ahead. The suitability and sustainability of any given agricultural technology depends on factors like resource availability and productivity, energy costs, and environmental constraints. The achievements of Green Revolution technologies in the 1960s and 1970s came at a critical time of impending food shortages, and the world’s people would be worse off without them. However, the rate of yield improvement for cereal production has been slowing since the mid-1980s.</p> <p>Looking ahead at the foreseeable circumstances under which 21st century agricultural producers must try to assure food security, there will be need for technologies that are less dependent on resources that are becoming relatively scarcer, like arable land and water, or becoming relatively more costly, like energy and petrochemical-based inputs. This paper considers agroecologically-based innovations that reduce farmers’ dependence on external inputs, relying more on endogenous processes and existing potentials in plants and soil systems. Such resource-conserving production represents a different approach to meeting food security goals.</p> <p>While these innovations are not yet fully understood and are still being researched, there are good agronomic reasons to account for their effectiveness, and scientific validations are accumulating. Enough successes have been recorded from making changes in the management of plants, soil, water and nutrients that more attention from researchers, policy-makers and practitioners is warranted, especially given the need to adapt to, and to mitigate the effects of, climate change. The same agroecological concepts and management methods that are enhancing factor productivity in rice production are giving similar results with other crops such as wheat, finger millet, sugarcane, mustard, and tef.</p> <p>Genetic potentials are the starting point for any and all agricultural production, and current efforts to improve food security and nutrition through plant breeding efforts should continue. However, future research and production strategies could beneficially seek to capitalize on biological processes and potentials existing within crops and in their supporting soil systems, rather than focusing so predominantly on making modifications in genetic factors. Scientific advances in the domains of microbiology, soil ecology and epigenetics could foreseeably assist farmers in meeting production and income goals with resource-economizing methods. It remains to be seen to what extent agroecologically-informed methods can help farmers meet expected agricultural production requirements to ensure global food security, but this direction deserves more attention and support.</p