CAR T-Cell Therapy for Hematologic Malignancies: Toxicities, Efficacy, and Opportunities
In this session, Dr. Corcoran focused on three main topics which are essential for integration of laboratory and clinical research to accelerate advances in drug development: understanding the effects of therapy in the tumor, overcoming therapeutic resistance, and molecular diagnostics to transform therapy.
For the first topic, he presented data of differential response rate of BRAF inhibitors in BRAF-mutated melanoma (>50%) and BRAF-mutated colorectal cancers (5%). Based on this differential clinical response, he discovered BRAF inhibitors alone do not inhibit phosphorylation of ERK (pERK) as effectively in colorectal cancer as in melanoma. Interestingly, even though concurrent inhibition and BRAF and MEK improved response rate against colorectal cancer, suppression of pERK was not as sufficient as single BRAF inhibition in melanoma cells in vitro. Getting to this key topic, here he looked at the entire pathways, the EGFR-BRAF-MAPK pathway in this case. Then he discovered that BRAF inhibitors are associated with a concurrent upregulation of EGFR, and feedback reactivation mechanisms of MAPK signaling pathway through EGFR limits the efficacy of BRAF-MEK cascade inhibition. These basic research findings resulted in the development of a triple blockade approach, and preclinical studies with combination BRAF and EGFR inhibitors and BRAF, MEK, and EGFR inhibitors have shown synergy to overcome adaptive resistance.
Then discussion moved on to overcoming therapeutic resistance. First, he showed several previously reported resistance mechanisms of BRAF-mutated colorectal cancers against BRAF inhibitors. However, multiple mutations tend to be seen within individuals and even within each specific tumor site due to tumor heterogeneity. In order to overcome multiple resistance mechanisms within a single individual, he demonstrated the importance of liquid biopsy to identify multiple resistance patterns. Elucidation of resistance mechanisms through circulating tumor DNA (ctDNA) analysis at multiple time points enables adaptation of targeted therapy in a real-time manner.
Lastly, he discussed recent approach to take advantage of molecular diagnostics to transform cancer therapy using the example of ctDNA. First, he introduced the effective use of ctDNA as an early marker for response to therapy. In the data he showed, the use of ctDNA at 4 weeks of therapy predicted response to therapy, suggesting that ctDNA may be used early in treatment in order to identify putative poor responders, which will allow them to alter treatment earlier and move to a more beneficial option. Second, he suggested the effective use of ctDNA analysis to identify individuals who may most benefit from adjuvant therapy.