UCLA researchers in the Department of Medicine have uncovered novel mechanism of acquired resistance against immune checkpoint blockade therapy in melanoma patients.
BACKGROUND:
Immune checkpoint blockade (ICB) therapy is a type of cancer immunotherapy that targets immune system components in order to reactivate immune cells to combat tumor cells. Despite the various FDA-approved therapies, a common challenge in ICB therapies is delayed relapses after initial anti-tumor response. The frequencies of acquired resistance to ICB is generally higher in cancer types that respond to ICB therapy at lower rates. Melanoma is a highly aggressive skin cancer that spreads throughout the body and is likely fatal if left untreated. After ICB therapy, acquired resistance occurs in an estimated 20-60% of responsive melanoma patients. Further clinical, correlative and preclinical studies are strongly needed to address the mechanisms of acquired resistance to improve patient prognosis and overall efficacy of ICB therapy. Strategies to address such mechanisms in melanoma are likely to benefit a wide variety of cancer types currently amenable to treatment with ICB therapy.
INNOVATION:
Researchers at UCLA conducted correlative/translational and preclinical studies entailing a genomic analysis of patient-matched normal and pre-and-post melanoma tissues as well as human and mouse experimental models of acquired ICB resistance. The study identified mutations specifically altered after acquired resistance to ICB such as anti-PD-1 anti-CTLA-4 therapy. Preclinical studies validated the functions of acquired-resistant gene mutations. Most notably, researchers found that recurrent deleted genes during relapse included genes that promote cell death and antigen-presenting genes. The same observations were made in clinical tumor samples as well as preclinical experimental model systems. Functional validation studies showed downregulation of these genes reduced human melanoma cytotoxicity by CD8 T cells. Both preclinical and clinical data converge to additional genetic mechanisms of acquired resistance. Further studies have investigated the genomic evolutionary mechanisms that engender tumor cell variants selected by ICB therapy to result in relapses. These evolutionary mechanisms reveal potential strategies to prevent cancer resistance development. Therefore, inhibiting anti-apoptotic proteins or stimulating proapoptotic proteins in combination with ICB therapy can be an effective strategy to reverse acquired resistance. Moreover, stabilizing the melanoma genome may be future strategy to prevent acquired resistance.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: Genetic analysis of 13 patient cohort and functional screens of human and mouse tumor models were synthesized for initial studies. Analysis of an expanded cohort of patients is underway, as well as broader mechanistic and functional studies and preclinical trials.