The overall goal of our research is to elucidate molecular and cellular mechanisms of antitumor activities of immuno-oncolytic viral vectors against metastatic tumors. We design novel approaches to enhance the antitumor efficacy of oncolytic virotherapy by expressing therapeutic genes such as the CXCR4 antagonist, augmenting spread of the virus within tumors, and designing novel therapeutic approaches by combining agents with both cytotoxic and immunogenic effects on tumor cells. The latter approach is intended to reprogram the tumor microenvironment to augment the level and persistence of spontaneously-induced antitumor immunity for long-term control of tumor progression. We anticipate that the oncolytic virotherapy-mediated changes in the tumor microenvironment will modulate the interaction between malignant and stromal cells and facilitate induction of protective antitumor immune responses. These studies, if successful, have the potential to be translated into the clinic though collaboration with our clinical investigators and will help in exploring the mechanistic underpinnings of tumor-immune system interactions.
As levels of oncolytic viruses attained within tumors are often significantly lower than those commonly achieved in vitro, strategies that improve intratumoral delivery and distribution of oncolytic viruses are likely to result in durable therapeutic responses. We examine whether altering tumor vascular function using photodynamic therapy (PDT) would allow for enhanced viral delivery and spread in vivo. Using syngeneic murine tumors and human tumor xenografts, we showed that the combination of PDT and oncolytic virotherapy inhibits the growth of primary tumors and metastatic disease. Vascular disruption induced by PDT was associated with increased viral replication in tumors and resulted in improved overall survival of animals compared to either monotherapy. We are currently exploring image-guided PDT in combination with armed oncolytic virotherapy for treatment of malignant glioma and investigate the effects of combination treatment on vascular function and inhibition of bone marrow-derived suppressive elements within the tumor microenvironment, which can ultimately overcome tumor-mediated immune suppression.
We have developed a peptide mimotope vaccine against the GD2 ganglioside to target neuroblastoma, which is the most frequent solid neoplasm in children that is responsible for approximately 15% cases of all pediatric tumors and has a poor prognosis in children above 1 year of age. We examine whether a novel immune response-modifying agent is capable of boosting efficacy of the mimotope vaccine to inhibit the spread of neuroblastoma in preclinical studies in mice. The findings of this study will illuminate a new paradigm for neuroblastoma immunotherapies aimed at the selective activation of inflammatory versus tumor-growth promoting immune cell that could increase therapeutic efficacy of anticancer vaccine in children with NB.
Tumor resistance represents a subclinical equilibrium achieved between host immunity and quiescent residual tumor cells that can extend for up to decades after treatment followed by disease relapse. Recurrences are often phenotypically different from the primary tumors, representing the end product of in vivo selection against continued sensitivity to a frontline treatment.
Being able to design carefully timed, second-line therapies targeting the recurrences would be of clinical value. Our studies have shown increased antitumor efficacy of the targeted delivery of the CXCR4 antagonist by oncolytic virotherapy against primary breast and ovarian tumors and spontaneous metastases compared to the conventional drug delivery approach. Specifically, we have shown that the armed oncolytic vaccinia virus was highly efficacious in treating metastatic tumors, and its multifaceted activities were associated with: (i) enhanced killing of cancer initiating cells, (ii) reduction of the tumor immunosuppressive network, and (iii) induction of antitumor humoral and cellular responses.
Altogether, the presented mechanism of inhibition of pathways promoting tumor growth is likely applicable to different cancer types and can potentially unravel novel therapeutic avenues that efficiently target cancer initiating cells to minimize the risk of tumor recurrence in cancer patients. Human tumor cell lines and subsequently clinical specimens from patients with recurrent tumors, who failed the frontline treatment with chemotherapy, will be included in the study to determine whether efficacy of the treatment is similar in a xenograft model.
Our hypothesis relies on combination treatment-induced changes in the tumor microenvironment that are conducive toward induction and preservation of antitumor immunity. Establishment of parameters in the tumor stroma that enhance adoptive immunotherapy will contribute to personalized approaches for successful treatment of relapse tumors. In summary, because the curative potential of antitumor treatments hinges on eradicating therapy-resistant variants in addition to counteracting the immunosuppressive microenvironment, if successful, the proposed research has an opportunity for rapid translation to the clinic. This innovative immune-based technology opens up the possibility of engineered oncolytic viruses that selectively infect tumor cells and express high concentrations of therapeutic molecules in metastatic tumors to potentiate the eradication of cancer.