YALE UNIVERSITY: Phase 2 Study of PARP Inhibition and Anti-PD-L1 Therapy in BRCAmt TNBC

Year of Grant: 2017

Location: United States

 

Approximately 5–10% of all newly diagnosed breast cancers in Western nations are hereditary, attributable primarily to inherited mutations in the BRCA1 and BRCA2 (BRCA1/2) genes. According to a recent meta-analysis, BRCA1/2 gene mutations are associated with a 40–57% lifetime risk of female breast cancer and an 18–40% lifetime risk of ovarian cancer.

It is also well established that BRCA1/2 carriers with breast cancer have markedly elevated risks of contralateral breast cancer of approximately

50% at 25 years post-diagnosis.

 

The clinical trial to which this proposal is attached is a randomized,

open-label phase II clinical trial exploring the effects of the anti-PD-L1

human monoclonal antibody atezolizumab with the PARP inhibitor

Veliparib either alone or in combination in 100 patients with BRCA1/2 mutated triple negative breast cancer (TNBC).  Patients with advanced

TNBC have a poor prognosis and no standard therapy is available.

Based on their preclinical studies, the applicant hypothesize that the combination of a DNA damage agent (PARP inhibitor) in TNBC patients

with mutations in DNA damage repair genes will increase the chances

of tumor response to anti-PD-L1 therapy.

 

Immune checkpoint blockade targeting CTLA-4 and PD-1 axis has revolutionized cancer treatment. Elevated pre-existent tumor immune infiltration, higher mutational loads and candidate neoantigens predicted from such DNA variants correlate with improved response and survival to checkpoint inhibitors in different tumor types. Emerging data indicate that the immunogenicity of tumors is prominently influenced by the load of somatic mutations and production of neoantigens that are presented by

the patient’s major histocompatibility complex (MHC) and recognized as “non-self” by the adaptive immune system, leading to tumor cell killing

upon immune reinvigoration using immune checkpoint blockade.

 

As part of this grant, the team will perform correlative studies including

the use of integrated biomarkers and exploratory biomarkers to be systematically measured in the tumor samples before and after treatment. The studies will be used to evaluate the tumor characteristics as well as

the immune contexture before and after treatment. They will also explore the possible connection between the biomarkers/patterns and patient performance after treatment to assess their clinical value.

 

In addition to producing a prominent clinical advancement, the study will demonstrate fundamental concepts linking DNA repair, specific genomic landscapes and anti-tumor immune response. Ultimately, the results from this study will support the clinical development of novel and biologically driven immunotherapies to treat TNBC. This application is requesting support only for genomic/transcriptomic profiling of the biopsy specimens from the clinical trial.