Issue No. 38, May 2021
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine, VCU and external experts focusing on important medically-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.     
Engineering T Cells to Express Tumoricidal MDA-7/IL-24 Enhances Cancer Immunotherapy.
A recent discovery published in Cancer Research by Drs. Wang and Fisher have demonstrated that arming T cells with tumoricidal and immune-potentiating MDA-7/IL-24 confers improved antitumor capabilities.
  • A novel cellular immunotherapy has been successfully developed by engineering T cells to produce human MDA-7/IL-24 that has profound tumor-specific cytotoxic effects in a broad spectrum of cancers.
  • Administration of MDA-7/IL-24-expressing T cells allows tumor-targeted delivery of MDA-7/IL-24 when T cells traffic to the tumor sites.
  • MDA-7/IL-24 engineered T cells acquire the unique capability to kill antigen-expressing cancer cells, as well as those that do not express the antigen, which can help eradicate tumor cells which down regulate antigen presentation.
  • MDA-7/IL-24 engineering also results in improved expansion of tumor-reactive T cells and heightened immunostimulatory state within the tumor sites.
  • This promising approach may be used to optimize the current cellular immunotherapies (adoptive T cell transfer, CAR T cell therapies) for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape.
Antigen-targeted cancer immunotherapy can be limited by immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Current cellular immunotherapies that use tumor-infiltrating lymphocytes or engineered Chimeric Antigen Receptor (CAR)-T cells, have shown limited efficacy in the treatment of solid cancers, which are known to be highly heterogenous and variable in antigen expression. To address this issue, the teams of Dr. Wang and Dr. Fisher collaboratively developed a new cellular immunotherapy by engineering T cells to produce a tumoricidal cytokine, i.e., melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24).

MDA-7/IL-24, originally discovered by Dr. Fisher’s laboratory, is a unique IL-10 family gene member that demonstrates profound antitumor effects against a broad spectrum of histologically distinct human cancers without harming normal cells. A phase I clinical trial in advanced cancers has established the safety and therapeutic efficacy of MDA-7/IL-24, when administered intratumorally by a non-replication competent adenovirus, supporting the potential for translation of MDA-7/IL-24 into the clinic as an experimental standalone therapy or its rational integration with other treatment regimens.

New research from Drs. Wang and Fisher published in Cancer Research describes a novel strategy of using MDA-7/IL-24-producing T cells as a personalized medicine to overcome the antigenic heterogeneity of solid cancers. This innovative multi-pronged approach will allow killing of cancer cells regardless of their expression of tumor antigens and also help reduce the escape of cancer cells from immune attack.
 
The investigators showed that MDA-7/IL-24-expressing T cells were superior to unmodified T cells in suppressing mouse prostate cancer and melanoma as well as cancer metastases. Hi-Myc transgenic mice that spontaneously develop prostate cancer was further used to evaluate the therapeutic potency of human MDA-7/IL-24-producing T cells. Different cohorts of 4-month-old Hi-Myc mice with presumed prostate cancer were treated with tumor-sensitized T cells that had been engineered to produce human MDA-7/IL-24 (Fig. 1A). Examination of the prostates after euthanizing animals at 6 months showed that T-MDA-7 therapy was more effective than mock engineered T cells (i.e., T-vec) at inhibiting prostate cancer progression, indicated by reduced weights of prostates (Fig. 1B). Administration of MDA-7/IL-24-producing T cells was associated with elevation of mRNA levels of human MDA-7/IL-24, and mouse Tnfa, and Ifng in prostate tissues, indicating trafficking of human MDA-7/IL-24-producing T cells to the tumor lesions as well as their activated status (Fig. 1C). Histology analysis of prostate tissues showed that treatment with MDA-7/IL-24-producing T cells significantly reduced progression of prostate cancer (Fig. 1D). Collectively, these findings indicate that MDA-7/IL-24-engineered T cells exhibit superior antitumor activity by counteracting multiple immune limiting factors in the tumor microenvironment and targeting cancer cells beyond an antigen-specific fashion (Fig. 1E).
Figure 1. Improved Control of Spontaneously Developed Prostate Cancer by MDA-7/IL-24-Producing T Cells. Schematic diagram of MDA-7/IL-24-engineered T cell therapy in Hi-Myc transgenic mice (A). Different cohorts of 4-month-old Hi-Myc transgenic mice received tumor-sensitized T cells that had been transduced with LV-vec (n=8) or LV-mda-7 (n=9) (once a week for a total of 4 doses). Animals were euthanized at 6 months and tumor burden was measured based on the weights of the prostates of individual mice (B). mRNA levels of human MDA-7/IL-24, and mouse Tnfa, or Ifng in prostate tissues were assessed by qRT-PCR (C). Representative H/E sections of prostate from each experimental group are shown (D). Data shown are representative of three independent experiments. * p < 0.05, ** p < 0.01, *** p < 0.001, NS, not significant using student t-test. E. A novel approach to improved T cell therapy. Antigen-specific or tumor-reactive T cells can inherently destroy cancer cells via CAR-directed antigen recognition and cytotoxicity (IFN-g, granzyme B). MDA-7/IL-24 engineering not only enhances T cell expansion or persistence within the tumors, but also allows T cells to acquire additional tumoricidal capacity and to eliminate antigen-negative variants. 
 
Publication:
 
* Liu Z, Guo C, Das SK, Yu X, Pradhan AK, Li X, Ning Y, Chen S, Liu W, Windle JJ, Bear HD, Manjili MH, Fisher PB, Wang XY. Engineering T Cells to Express Tumoricidal MDA-7/IL24 Enhances Cancer Immunotherapy. Cancer Res. 2021 May 1;81(9):2429-2441. PMID: 33727225 DOI: 10.1158/0008-5472.CAN-20-2604
 
About the Investigators: Paul B. Fisher, MPh, PhD, FNAI, is Professor and Chair of the VCU Department of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Xiang-Yang Wang, PhD, is Harry and Judy Wason Distinguished Professor of HMG; Associate Scientific Director for Immunology, VCU Institute of Molecular Medicine and Co-leader, Developmental Therapeutics Program, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA. Dr. Zheng Liu, is a postdoc in the HMG, the first author of this paper, and performed much of the biological and animal work. Chunqing Guo, PhD, is an Assistant Professor in HMG and equally contributed to this research study. Jolene J. Windle, PhD, is the Irene Shaw Grigg Professor of Genetics in HMG. Harry D. Bear, MD, PhD, is the Walter Lawrence, Jr. Distinguished Professor in Oncology, Chairman of the Division of Surgical Oncology. Masud Manjili, PhD, DVM, Professor in the department of Microbiology and Immunology. This study was supported in part by Department of Defense Prostate Cancer Research Awards (W81XWH-11-1-0481, W81XWH-13-1-0162), National Cancer Institute grants (CA229812, CA099326, CA259599), VCU Massey Cancer Center Research Development Funds, the National Foundation for Cancer Research, and National Cancer Institute Cancer Center Support Grant to VCU Massey Cancer Center P30CA16059.