Combining Th1 specific multi-antigen cancer vaccines and radiation for liposarcoma treatment

Liposarcomas (LPS) are classified in three principal subtypes: pleomorphic, myxoid/round cell and well-differentiated/de-differentiated (WD/DD); each of them with different clinical behavior, treatment sensitivity and underlying biology. WD/DD LPS comprises approximately 40% of LPS and most commonly arise in the retroperitoneum. Surgical resection is the primary management strategy for localized retroperitoneal LPS, but most patients experience local or metastatic disease progression within 5 years of diagnosis. The role of adjuvant therapy is not well established, and only a quarter of patients receive neoadjuvant or adjuvant radiotherapy (RT). Given challenges with local recurrence and metastatic disease in LPS, development of novel therapies is urgently needed.

Emerging phase III results from the EORTC STRASS trial show neoadjuvant RT prior to LPS resection improves 3-year local control compared to resection alone. RT is a well-known immune modulator that augments tumor antigen presentation in a variety of cancers and our preliminary data shows that RT increases the percentage of CD3+ and CD4+ T cells in sarcoma tumors. However, LPS have a low mutational burden with few neoantigens available; therefore, RT alone might not induce a sufficient anti-tumor immune response to eliminate cancer cells. Cancer vaccines can boost anti-tumor immunity. LPS have characteristic amplifications in MDM2, CDK4 and HMGA2 genes that drive tumorigenesis. Overexpressed, non-mutated proteins in tumors can induce tumor-specific immunity and are good candidates for tumor vaccine development. A strong inflammatory response mediated by Type 1 (Th1) CD4+ T-cells is needed for effective anti-tumor immune response, and our group has developed a method to identify tumor antigen epitopes to elicit Th1-specific immunity. Importantly, we have already shown in mouse models and Phase I/II trials that we can induce Th1 immunity against MDM2. STEMVAC, a multi-antigen vaccine including MDM2 Th1 epitopes, in addition to 4 other cancer stem cell antigens, has demonstrated immunogenicity and safety in Phase I/II studies with breast cancer patients.