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2017 ; 7
(1
): 14186
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Development of a Curative Therapeutic Vaccine (TheraVac) for the Treatment of
Large Established Tumors
#MMPMID29079801
Nie Y
; Yang D
; Trivett A
; Han Z
; Xin H
; Chen X
; Oppenheim JJ
Sci Rep
2017[Oct]; 7
(1
): 14186
PMID29079801
show ga
Harnessing immune system to treat cancer requires simultaneous generation of
tumor-specific CTLs and curtailment of tumor immunosuppressive environment. Here,
we developed an immunotherapeutic regimen capable of eliminating large
established mouse tumors using HMGN1, a DC-activating TLR4 agonist capable of
inducing anti-tumor immunity. Intratumoral delivery of HMGN1 with low dose of
Cytoxan cured mice bearing small (????0.5?cm), but not large (????1.0?cm) CT26
tumors. Screening for activators capable of synergizing with HMGN1 in activating
DC identified R848. Intratumoral delivery of HMGN1 and R848 plus Cytoxan
eradicated large established CT26 tumors. The resultant tumor-free mice were
resistant to subsequent challenge with CT26, indicating the generation of
CT26-specific protective immunity. This immunotherapeutic regimen caused homing
of tumor-infiltrating DC to draining lymph nodes and increased infiltration of T
cells into tumor tissues. Cytoxan in this regimen could be replaced by
anti-CTLA4) or anti-PD-L1. Importantly, this immunotherapeutic regimen was also
curative for large established mouse Renca and EG7 tumors. Thus, we have
developed a curative therapeutic vaccination regimen dubbed 'TheraVac' consisting
of HMGN1 and R848 plus a checkpoint inhibitor, that can, without using exogenous
tumor-associated antigen(s), eliminate various large tumors and induce
tumor-specific immunity.