Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Abstract

Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here, we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO À TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40 and (ii) a decrease of IDO enzyme activity produced by nontumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy.

The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenance

“…To determine whether intra-tumoral T cells changed with D-1MT treatment, we used the pan T cell marker CD3. Similar to prior results in a syngeneic murine model of lung cancer 22 , we found no change in CD3 pos T cell frequency or absolute number with D-1MT treatment (Fig. 1D).…”

“…C57BL/6 mice (The Jackson Laboratory) were housed in a pathogen-free environment, and experimental protocols were approved by the Johns Hopkins Institutional Animal Care and Use Committee. Similar to others studying the role of IDO1 in cancer 21,22 , female mice were used.…”

Targeting the IDO1 pathway in cancer: from bench to bedside

“…Administering indoximod with the PD-1 antibody pembrolizumab (Keytruda) led to a 61% overall response rate, including 10 complete responses (20%) and 21 partial responses (41%), in patients with advanced melanoma. The median progression-free survival under combinatorial treatment was 12.9 months, with a 1-year rate of 56%, suggesting a synergistic antitumor therapeutic effect [ 71 ].…”

Reshaping the tumor microenvironment with oncolytic viruses, positive regulation of the immune synapse, and blockade of the immunosuppressive oncometabolic circuitry

“…The addition of IDO inhibitors is required to induce anticancer effects in several models of cancer. For example, HPV16-E6-E7/HRAS-driven lung epithelial cancer was suppressed by only the combination of HPV16 E7 vaccines, OX40 agonists, and IDO inhibitors 63 . Furthermore, Berrong et al 63 showed that while the addition of anti-OX40 to an antigen-specific cancer vaccine moderately enhanced therapeutic efficacy, it was the addition of an IDO inhibitor to this treatment that eventually led to complete regression of established tumors in 60% of treated mice.…”

“…For example, HPV16-E6-E7/HRAS-driven lung epithelial cancer was suppressed by only the combination of HPV16 E7 vaccines, OX40 agonists, and IDO inhibitors 63 . Furthermore, Berrong et al 63 showed that while the addition of anti-OX40 to an antigen-specific cancer vaccine moderately enhanced therapeutic efficacy, it was the addition of an IDO inhibitor to this treatment that eventually led to complete regression of established tumors in 60% of treated mice. Additionally, in agreement with our data, Sagiv-Barfi and colleagues combined intratumoral delivery of an adenovirusrelated TLR9 ligand with OX40 activation to increase anticancer T cell responses 64 .…”