posted on 2022-01-03, 13:04authored byEdward
C. Koellhoffer, Chenkai Mao, Veronique Beiss, Lu Wang, Steven N. Fiering, Christine E. Boone, Nicole F. Steinmetz
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.