JITC Editor Picks
Jianshu Wei, Can Luo, Yao Wang, Yelei Guo, Hanren Dai, Chuan Tong, Dongdong Ti, Zhiqiang Wu & Weidong Han
Journal for ImmunoTherapy of Cancer, 7:209 (7 August 2019)
Short hairpin RNA (shRNA)-mediated silencing of PD-1 allowed for investigation of the impact of PD-1 signaling on the behavior of CAR T cells by Wei et al. In in vitro co-culture experiments, the blockade of PD-1 was not found to enhance the cytotoxicity of the CD19-targeted CAR T cells; rather, while the CAR T cells had significantly increased resistance to PD-L1-mediated immunosuppression, the PD-1-knockdown CAR T cells were less effective at killing CD19-positive tumor cells, especially at low CAR T-to-tumor cell ratios. These findings were mirrored in vivo, where decreased CAR T cell proliferation and differentiation resulted in low CAR T cell expansion and weak tumor clearance. These findings point to the many roles of PD-1 signaling in anti-tumor immunity and T cell function.
Suzanne Thomas, Linta Kuncheria, Victoria Roulstone, Joan N. Kyula, David Mansfield, Praveen K. Bommareddy, Henry Smith, Howard L. Kaufman, Kevin J. Harrington & Robert S. Coffin
Journal for ImmunoTherapy of Cancer, 7:214 (10 August 2019)
Oncolytic viruses have been employed to increase the immunogenicity of cell death and to induce systemic host anti-tumor immunity. Thomas et al developed a new HSV-1-based oncolytic immunotherapy with potent anti-tumor capabilities. The new strain was engineered to express the envelope glycoprotein of gibbon ape leukemia virus, leading to immunogenic cell death in vitro as well as local and distant tumor responses in in vivo preclinical models. Further engineering of the virus to express mGM-CSF along with mCTLA-4, mCD40L, m4-1BBL, or mOX40L led to increased anti-tumor activity, particularly evident in non-injected tumors. The developed HSV-1-based platform thus offers a flexible approach for future development of oncolytic immunotherapies.
Yousef R. Badran, Justine V. Cohen, Priscilla K. Brastianos, Aparna R. Parikh, Theodore S. Hong & Michael Dougan
Journal for ImmunoTherapy of Cancer, 7:226 (22 August 2019)
The emergence of immune-related adverse events, particularly immune-related enterocolitis (irEC), often prompts disruption or discontinuation of immune checkpoint inhibitors (ICIs). Traditional first-line treatment of irEC includes steroid treatment, but some patients do not respond and there are well-known drawbacks of long-term steroid use. Therefore, blockade of TNF-alpha presents an alternative option; however, there is limited data on the impact of this blockade when administered concurrently with ICIs on treatment outcomes. Badran et al report a case series of five patients treated with first-line steroids and then concurrent TNF-alpha blockade and ICIs, demonstrating symptom and disease control with the combination. This combination might be interesting by facilitating steroid tapering and preventing immune related enterocolitis. These results are in line with recent observations in pre-clinical studies (Perez-Ruiz et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature 2019).
Daruka Mahadevan, Mark C. Lanasa, Charles Farber, Manjari Pandey, Maria Whelden, Susan J. Faas, Terrie Ulery, Anjli Kukreja, Lan Li, Camille L. Bedrosian, Xiaoping Zhang & Leonard T. Heffner
Journal for ImmunoTherapy of Cancer, 7:227 (23 August 2019)
CD200, found on a range of cell types including B cells, T cells, and dendritic cells, and also overexpressed by a variety of tumor cells, acts to inhibit immune activity upon ligation with its receptor, CD200R. Therefore, samalizumab, a recombinant humanized monoclonal antibody binding CD200, was explored in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) patients by Mahadevan et al. Using a 3+3 study design, dose levels from 50 to 600 mg/m2 were explored, with safety, maximum tolerated dose, and pharmacokinetics as the primary endpoints. An ORR of 4% was observed in CLL patients, with another 70% of the CLL patients exhibiting stable disease. No MM patients responded to the therapy. With further optimization of the dosing regimen, samalizumab may hold promise for immune checkpoint blockade therapy in the future.
Minjun C. Apodaca, Amy E. Wright, Angela M. Riggins, William P. Harris, Raymond S. Yeung, Lei Yu & Chihiro Morishima
Journal for ImmunoTherapy of Cancer, 7:230 (28 August 2019)
High levels of circulating myeloid-derived suppressor cells (MDSCs) have been correlated with poor outcomes for cancer patients, making them a promising biomarker. However, there is currently wide variation in quantification of MDSCs amongst laboratories. Apodaca et al herein propose a whole blood, flow cytometry-based assay for quantification of MDSCs. Using their nine color, 11 parameter assay, a few pre-analysis variables were identified to have a large impact on MDSC measurement. Longer elapsed time since collection of whole blood reduced the number of identified MDSCs, as did the use of Na+heparin tubes instead of K2EDTA. These findings, along with the proposed gating strategy, hold promise to help standardize quantification of this important cell population.