SUMMARY:
Researchers from UCLA’s David Geffen School of Medicine have discovered a novel regimen using MAPK inhibition and immune checkpoint therapy for the treatment of melanoma and other cancers. Furthermore, they have outlined cellular targets in the tumor microenvironment with key roles in improving sensitivity to therapy.
BACKGROUND:
Programmed cell death protein-1/programmed death-ligand 1 (PD-1/L1)- and mitogen-activated protein kinase (MAPK)-targeted therapies have revolutionized the treatment of various cancers, notably improving the outcomes of BRAFV600* malignancies. For melanoma, wherein 50% of cases harbor BRAFV600* mutations, advanced standards of care consisting of MAPK inhibitors have increased the 5-year survival rate to almost 30%, but it remains low because the majority of patients acquire resistance to treatment within one year. Immune checkpoint therapy (ICT) with anti-PD-1 agents results in a more potent and sustained response in the 30%–40% of responding patients with BRAFV600 melanoma. Furthermore, recent data has shown that combination ICT with anti-PD-1 + anti-CTLA-4 agents reduces the rate of innate resistance from 60%–70% to 40%–50%. Current laboratory work and clinical trials are now focused on assessing the effects of combination therapy using anti-PD-1/L1 and MAPK inhibitors; however, the optimal timing, drug regimen, and sequence of administration for such combination therapies have yet to be elucidated.
INNOVATION:
UCLA researchers led by Dr. Roger Lo in the School of Medicine have developed a strategy combining PD-1/L1- and MAPK-targeted therapies to enhance and overcome resistance to treatment for melanoma. They tested various sequential and/or combinatorial regimens in subcutaneous murine tumor models driven by BRAFV600 and found a regimen that led to increased anti-tumor efficacy, suppression of therapeutic resistance, and increased response durability. Using this regimen, the researchers also observed activity against melanoma brain metastasis. They further validated their findings in other cancer models including an Nras mutant, Nf1 mutant melanoma, as well as Kras mutant colorectal carcinoma and pancreatic ductal adenocarcinoma. Additionally, the researchers sampled the treated tumors and used immune cytometry by time-of-flight (CyTOF) to identify the specific tumor-associated macrophage (TAM) subpopulations that were elicited by the regimen. Taken together, the researchers present an alternative immunotherapy strategy with high antitumor efficacy that could have immediate clinical implications for melanoma and other cancers.
POTENTIAL APPLICATIONS:
• Treatment of primary and metastatic melanoma
• Identified TAM co-targets can be used for development of novel therapies
• Can help induce sensitivity in what would previously have been cold tumors
ADVANTAGES:
• Improved initial base response to therapy
• Increases the therapeutic timeline where drugs are effective
DEVELOPMENT-TO-DATE:
Method has been tested and shown efficacy within in vivo models. Associated co-targets have been validated in vitro.
Related Papers (from the inventors only):
Wang, Yujue et al. “Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.” Cancer cell vol. 39,10 (2021): 1375-1387.e6. doi:10.1016/j.ccell.2021.07.023