Background: Blockade of the programmed death-1 (PD-1) pathway has shown efficacy across a range of tumor types. However, some tumors do not respond and a combination strategy with other treatments may be required. CD38, a leukocyte receptor and ectoenzyme, was recently shown to be upregulated following PD-1 pathway blockade in mouse tumor models (Chen et al. ASCO-SITC 2017). Daratumumab is a fully human monoclonal antibody (mAb) that binds to CD38. It has been shown to exhibit immunomodulatory properties in patients with multiple myeloma (Krejcik et al. Blood. 2016). Studies in syngeneic mouse models and in vitro assays were conducted to investigate the potential of targeting CD38 in combination with anti-PD-1 to increase antitumor response. Methods: mAbs targeting mouse CD38 (mCD38-mg2a; mCD38) and mouse PD-1 (mPD1-mIgG1-D265A; mPD-1) were tested alone or in combination in several syngeneic models: colon adenocarcinoma (MC38), plasmacytoma (J558), and lung carcinoma (M109). The effect of these mAbs on the phenotype and functionality of tumor-infiltrating and circulating lymphocytes was evaluated using flow cytometry and immunohistochemistry. In addition, the effect of daratumumab on human regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) was assessed. Results: Combined anti-mCD38/anti-mPD-1 mAb treatment enhanced tumor regression and extended survival compared with single-mAb treatment in mouse tumor models. In the MC38 model (n=10/group), 55% of mice were tumor free (TF) following combined treatment, whereas 0% and 25% were TF following individual administration of anti-mCD38 or anti-mPD-1 mAbs, respectively. Similar effects were observed in J558- and M109-bearing mice (n=10/group for both models): with combined treatment, 85% of J558 and 20% of M109 mice were TF, compared with 50% (J558) and 0% (M109) for anti-mCD38 and 25% (J558) and 0% (M109) for anti-mPD-1 mAbs, respectively. Enhanced antitumor activity with combination treatment was associated with increased infiltration and activation of intratumoral CD4+ and CD8+ T cells, as well as increased levels of Ki67 on circulating T cells in MC38 and J558 models. The antitumor activity of anti-mCD38 mAb was dependent on active Fc function, suggesting that CD38+ cells may limit antitumor response. Consistent with this hypothesis, anti-mCD38 mAb led to a reduction in the frequency of CD38+ immunosuppressive Tregs and MDSC populations in mice. In vitro, daratumumab mediated antibody-dependent cellular cytotoxicity of human Tregs and led to the depletion of human monocytic MDSCs in blood of patients with lung cancer (n=17). Conclusion: These results demonstrate the combined effect of targeting both CD38 and PD-1 pathways in regulating antitumor immunity, and suggest that dual targeting of CD38 with daratumumab and PD-1 with nivolumab may represent a promising combination strategy for treating cancer. Citation Format: Natalie A. Bezman, Michelle Kinder, Amy D. Jhatakia, Bethany K. Mattson, Darlene Pizutti, Edward W. Thompson, Dorie A. Capaldi, Mark W. Mendonca, Aravind Anandam, Gopal Dhar, Lavanya Kovvuri, Archana Devi, Swagatam Ray, Vivek Surse, Elizabeth Saravia, Robert F. Graziano, Natalie A. Hutnick, Alan Korman. Antitumor activity associated with dual targeting of CD38 and programmed death-1 (PD-1) pathways in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1727.

In recent years, the demand of chilli has tremendously increased due to its attractive market price and multifarious used in cooked and processed forms. At present people are much concerned about the fruit quality and yield. Therefore, attention is being paid for development of genotypes having high yield potential with desirable fruit quality characters in a short period of time. For this purpose, seeds of chilli were mutagenised with ethyl methane sulphonate (EMS) and diethyl sulphate (DES) to determine their mutagenic sensitivity in M 1 generation. The increasing concentration of EMS and DES decreased in morphological and yield characters. The spectrum of mutation and induced variability for various quantitative traits were observed in M 1 generation such as germination (%), plant height, primary and secondary branches per plant, days to first flowering, fruit length (cm), fruit girth (cm), total number of fruits per plant, number of seeds per fruit, seed weight per fruit (g), 100 seed weight (g) and pericarp: seed ratio showed variability in chilli with the effect of EMS and DES. The percentage of chromosomal abnormalities in different mitotic stages was significantly higher than that of the control in all the treatment concentrations.

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