Improving the response to cancer immunotherapy by reactivating the 'guardian of the genome'

The p53 protein earned the nickname “guardian of the genome” because it plays a key role in DNA damage response by preventing cells with faulty DNA from dividing. Mutations or malfunctions in p53 have been implicated in many types of human cancers.

In some tumors, normal p53 function is blocked by high levels of another protein called MDM2. Now, scientists from the Karolinska Institutet in Sweden and U.S. biotech Aileron Therapeutics have early evidence that reactivating p53 by inhibiting MDM2 with a drug developed by the company could boost the immune response against tumors. They reported their findings in the journal Cancer Discovery.

Based on positive results in mice and patient tissue samples, the researchers suggested that the MDM2 inhibitor could be used alongside checkpoint inhibitors to help more cancer patients benefit from immuno-oncology agents.

The p53 protein protects against genomic changes in part by blocking repetitive DNA elements that could alter the human genome. These include sequences known as endogenous retroviruses, which were incorporated into the human genome from ancestral infections.

The Karolinska-led team was surprised to discover that p53 could induce the expression of endogenous retrovirus sequences in different cancer cell lines from breast cancer, osteosarcoma, colon cancer and melanoma.

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The researchers went on to explore reactivating p53 with MDM2 inhibitors in lab dishes. “When we blocked the suppressor MDM2, p53 activated endogenous retroviruses which induced antiviral response and boosted the production of immune-activating interferons,” Galina Selivanova, the study’s senior author, explained in a statement.

Interferons are inflammatory molecules needed for effective immune responses. They're also major regulators of tumor-infiltrating immune cells, the researchers noted. In addition to affecting interferons and related genes, p53 activation enhanced antigen presentation and processing, which could prime cancer cells for targeting by the immune system, the team showed.

Based on those findings, the scientists figured the method might work well with PD-1 inhibition, which lifts the brakes that tumors impose on the immune system.

 Using an MDM2 inhibitor developed by Aileron alongside a PD-1 inhibitor markedly reduced tumor growth in mice with melanoma that were resistant to immune checkpoint blockade, the team found.

In another mouse model of colon cancer, treatment with Aileron’s ALRN-6924, an advanced analog of the drug, promoted the recruitment of tumor-infiltrating immune cells, especially CD8+ killer T cells, as well as an increase of tumor-suppressing M1 macrophages, the team reported. Combining the drug with a PD-1 inhibitor also produced a complementary anti-tumor effect.

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ALRN-6924 is in a phase 1b trial to prevent adverse bone marrow effects in patients undergoing chemotherapy. The Karolinska-led team analyzed biopsy samples from two melanoma patients in the trial before and after treatment. They found p53 was activated in tumors and that the interferon pathway and activity of other genes related to the anti-tumor immune response were enhanced.

“This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies,” Selivanova said in a statement. “A combination of these can be particularly important for patients who don’t respond to immunotherapy.”

Aileron recently launched another phase 1b trial in patients with p53-mutated non-small cell lung cancer. The trial is testing ALRN-6924 as a protective agent for patients undergoing chemotherapy with or without immune checkpoint inhibitors.

Many other companies have MDM2 inhibitors in their arsenals. These include Roche’s idasanutlin, which failed a phase 3 acute myeloid leukemia (AML) trial last year. Through a licensing deal last year, Rain Therapeutics gained rights to Daiichi Sankyo’s milademetan (DS-3032). And Novartis is developing siremadlin (HDM201), while Amgen has AMG 232.

Selivanova is a co-founder of Boston biotech Aprea Therapeutics. The company is developing a p53 reactivator dubbed eprenetapopt (APR-246). The drug, used in tandem with AbbVie and Roche’s Venclexta and Celgene’s Vidaza, just reported a win from a phase 1/2 trial in TP53-mutant AML.