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Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot.

ABSTRACT: Oncolytic viruses, colloquially referred to as "living drugs", amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruses to prime and augment their activity. This review focuses on adenoviruses, the most clinically investigated of all the oncolytic viruses. It covers specific design features of clinical adenoviral candidates and highlights their potential both alone and in combination with checkpoint inhibitors in clinical trials to turn immunologically "cold" and unresponsive tumors into "hotter" and more responsive ones through a domino effect. Finally, a "mix-and-match" combination of therapies based on the paradigm of the cancer-immunity cycle is proposed to augment the immune responses of oncolytic adenoviruses.

SUBMITTER: Oronsky B

PROVIDER: S-EPMC9562194 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot.

Oronsky Bryan B Gastman Brian B Conley Anthony P AP Reid Christopher C Caroen Scott S Reid Tony T

Cancers 20220927 19

Oncolytic viruses, colloquially referred to as "living drugs", amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruse ...[more]

PMID: 36230621

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Project description:Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10-15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.

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Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot.

Publications

Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot.

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