“Conventional therapy tends to reduce tumor burden and improves symptoms but may fail to eradicate tumor-initiating cells, leading to eventual recurrence and drug resistance,” they suggested. “Therapies targeting tumor-initiating cells may, therefore, work best alongside conventional therapies that debulk the tumor mass.”
Such debulking steps may be particularly important for solid tumors, adds Stern, as therapeutics like antibodies are quite large and can be limited in their capacity to reach the target cells. Initially shrinking the tumors using chemotherapy might facilitate immunotherapeutic access.
NeoTX Therapeutics and Active Biotech, meanwhile, are working on immunotherapy with naptumomab, which fuses the Fab fragment of an antibody targeting 5T4 with an engineered bacterial superantigen that activates T cell responses.
In preclinical studies, naptumomab has shown synergistic anti-tumor effects and has extended overall survival when combined with checkpoint inhibition.
At the 2018 AACR meeting, researchers tested naptumomab and an anti-PD-1 as monotherapy or in combination in low immunogenic mouse tumor models. Although naptumomab alone showed some capacity to activate T cells and increase tumor infiltration and the anti-PD-1 had no effect, the combination more dramatically increased serum cytokines and CD8:CD4 ratio in the tumors, resulting in reduced tumor burden and prolonged media survival.
Findings like these led to a Phase 1b/2 clinical trial, currently recruiting, that combines naptumomab with AstraZeneca’s anti-PD-1 durvalumab versus advanced and metastatic solid tumors. The first patient in this study was dosed last October.
“The dosing of the first patient in our Phase 1b trial is a significant milestone for NeoTX, as it is our first clinical-stage molecule developed with our Selective T Cell Redirection (STR) platform,” said company CEO Asher Nathan in announcing the milestone. “Previous clinical studies have shown Nap to be well tolerated, and preclinical work conducted by the NeoTX team supports its broad potential in treating advanced and metastatic tumors, especially in combination with checkpoint inhibitors.”