We have been developing novel immunotherapeutic molecules, antibodies and armed antibodies by protein engineering. We have established mouse tumor models expression various oncogenic receptors to mimic clinical tumors. My lab had made significant progress in understanding how traditional cancer therapies both rely on and impact the immune system. I strongly believe that a thorough understanding of immunity during current standard-of-care treatments is imperative if immunotherapeutics are to be clinically successful.
Current standard cancer therapies often fail to clear advanced cancers. Most recent studies have focused on combining conventional drugs or adding other treatment such as irradiation and oncogenic receptor blockades. Unfortunately, even with these strategies, relapse often occurs.
Within the last 10 years, I have led investigations into the mechanisms underlying tumor relapse and treatment resistance (two related clinical problems) after intensive standard treatment, such as irradiation and chemotherapy, or more novel immunotherapies. We learned that while tumor selection could be intrinsic, tumor evasion could also evolve from the extrinsic changes to the microenvironment created after treatment.
We have been focused on understanding these poorly defined changes within the tumor microenvironment after conventional anti-cancer treatment. Indeed, despite initial control of tumor growth by conventional therapies, relapse still frequently occurs due to various immune suppressive pathways that take place over time, including the lack of sufficient dendritic cell (DC)/T cell infiltration, newly developed treatment-associated resistance, or an increase in the number of M2 tumor-associated macrophages within well-established tumor tissues.
Current immunotherapy has been difficult to integrate into standard-of-care since many conventional drugs and treatments suppress immune responses. Until the recent anti-CTLA4 and anti–PD-1/PDL-1 trials, immunotherapy has always been viewed as a last resort therapeutic option. Without understanding the impact of current treatments on immunity, potentially potent, immunotherapeutics may fail to show promising effects.
However, from our work in understanding the mechanisms underlying tumor-evolved evasion, we can now design new strategies that will better integrate intensive conventional therapies with immunotherapies, the combination of which can more effectively kill tumor cells while optimally mobilizing host immunity to achieve complete tumor regression and prevention of metastasis.