CAR T-Cell Therapy for Hematologic Malignancies: Toxicities, Efficacy, and Opportunities
Despite preclinical efficacy, therapies often fail to achieve impactful outcomes in clinical practice. Dr. Corcoran explored this concept in detail using his research on colorectal cancer as a relevant model of therapeutic resistance to inhibition of driver mutations. Broadly, therapies targeting specific driver mutations may “fail” due to incorrect target selection, target relevance in only select patients, insufficient therapeutic window, or a lack of sufficient target engagement. Moreover, cellular and environmental context may also play an important role in mechanisms of resistance.
BRAF mutations are commonly seen in both colorectal cancer (8-10%) and melanoma (50%). Early studies in melanoma demonstrated that BRAF mutant inhibitors can lead to sustained inhibition of the MAPK/ERK signaling pathway, though this appears to be more transient in colorectal cancer with poor response rates (<10%), perhaps suggesting an oncogenic pathway addiction in these tumors. In order to circumvent acquired resistance from downstream signaling molecules, combinatorial of BRAF and MEK was used to try to deepen patient responses, as this has been successful in melanoma. However, response rates in patients with colorectal cancerwere only modestly increased from approximately 5% with BRAF inhibitor monotherapy to 12% with BRAF/MEK inhibitor combinations.
While somewhat encouraging, further investigation was needed to elucidate why colorectal tumors are relatively unresponsive to targeting of a driver pathway. In vitro data demonstrated that this is, in part, due to insufficient suppression of the MAPK/ERK signaling pathway, as dual inhibition on leads to an approximate 50% reduction in downstream signaling, as compared to over 85% in melanoma.
Dr. Corcoran demonstrated that colorectal cancer, unlike melanoma, has increased activation of receptor tyrosine kinases (RTKs) in response to MAPK/ERK pathway inhibition. This provided biological rationale to combine BRAF and EGFR inhibition, which ultimately led to deeper and more sustained inhibition of signaling along with better response rates in patients up to 30%. This concept of RTK activation appears to also be true in KRAS mutated tumors; KRAS inhibitors can achieve response rates up to 40% in patients with KRAS mutated lung cancer, though this is decreased 2-3-fold in patients with colorectal cancer. Again, co-inhibition of KRAS and EGFR improves these response rates.
Although we often study target alteration or adaptive feedback mechanisms in vitro, this may limit our understanding of therapeutic resistance observed clinically, as intratumoral or intertumoral heterogeneity can play a significant role in treatment failure. While resection specimens can sometimes identify intratumoral heterogeneity, the more frequent use of core needle biopsies can miss these findings. Furthermore, recent studies on intratumoralheterogeneity have been better illustrated by single cell and spatial studies, which are not yet in routine clinical use. Nevertheless, circulating tumor DNA (ctDNA) is a promising avenue by which to better identify both intratumoral and intertumoral heterogeneity. Indeed, liquid biopsies combining both ctDNA detection with targeted ddPCR of select driver mutations could identify resistance mechanisms in 70-80% of cases.
The future applications of these studies and emerging technologies are broad. Using clinically derived organoid models, Dr. Corcoran showed data highlighting the importance of local immune response in colorectal cancer and explored ongoing studies combining immunotherapy with either BRAF/MEK or BRAF/EGFR inhibition, which improved response rates to 25% and 50%, respectively. Furthermore, ctDNA is becoming increasingly used in clinical practice. One example in colorectal cancer is the use of adjuvant therapy after curative intent therapy for stage II and III patients, which remains controversial.
Recently, the DYNAMIC study demonstrated that residual ctDNA after resection of stage II colorectal cancer was highly prognostic, and ctDNA-negative patients could be spared adjuvant therapy. These findings were corroborated by the independent GALAXY study, and researchers in other malignancies, including hematologic malignancies, have ongoing efforts to better define standardized metrics for molecular measurable residual disease and how these can be used to personalize treatments for patients.