| Autor: |
Koellhoffer EC; Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States., Mao C; Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, United States., Beiss V; Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States., Wang L; Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States., Fiering SN; Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, United States.; Norris Cotton Cancer Center, Geisel School of Medicine and Dartmouth Hitchcock Medical System, Lebanon, New Hampshire 03755, United States., Boone CE; Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States., Steinmetz NF; Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States.; Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States.; Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States.; Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, United States.; Center for Nano-ImmunoEngineering, University of California, San Diego, La Jolla, California 92093, United States.; Institute for Materials Design and Discovery, University of California, San Diego, La Jolla, California 92093, United States. |
| Abstrakt: |
Viral immunotherapies are being recognized in cancer treatment, with several currently approved or undergoing clinical testing. While contemporary approaches have focused on oncolytic viral therapies, our efforts center on the development of plant virus-based cancer immunotherapies. In a previous work, we demonstrated the potent efficacy of the cowpea mosaic virus (CPMV), a plant virus that does not replicate in animals, applied as an in situ vaccine. CPMV is an immunostimulatory drug candidate, and intratumoral administration remodels the tumor microenvironment leading to activation of local and systemic antitumor immunity. Efficacy has been demonstrated in multiple tumor mouse models and canine cancer patients. As wild-type CPMV is infectious toward various legumes and because shedding of infectious virus from patients may be an agricultural concern, we developed UV-inactivated CPMV (termed inCPMV) which is not infectious toward plants. We report that as a monotherapy, wild-type CPMV outperforms inCPMV in mouse models of dermal melanoma or disseminated colon cancer. Efficacy of inCPMV is less than that of CPMV and similar to that of RNA-free CPMV. Immunological investigation using knockout mice shows that inCPMV does not signal through TLR7 (toll-like receptor); structure-function studies indicate that the RNA is highly cross-linked and therefore unable to activate TLR7. Wild-type CPMV signals through TLR2, -4, and -7, whereas inCPMV more closely resembles RNA-free CPMV which signals through TLR2 and -4 only. The structural features of inCPMV explain the increased potency of wild-type CPMV through the triple pronged TLR activation. Strikingly, when inCPMV is used in combination with an anti-OX40 agonist antibody (administered systemically), exceptional efficacy was demonstrated in a bilateral B16F10 dermal melanoma model. Combination therapy, with in situ vaccination applied only into the primary tumor, controlled the progression of the secondary, untreated tumors, with 10 out of 14 animals surviving for at least 100 days post tumor challenge without development of recurrence or metastatic disease. This study highlights the potential of inCPMV as an in situ vaccine candidate and demonstrates the power of combined immunotherapy approaches. Strategic immunocombination therapies are the formula for success, and the combination of in situ vaccination strategies along with therapeutic antibodies targeting the cancer immunity cycle is a particularly powerful approach. |
