New insights surrounding a particular protein could help to broaden the range of effective immunotherapy treatments available for cancer patients.
Researchers from the Karolinska Institutet in Sweden have found that the pharmacological activation of the protein p53 boosts the immune response against tumours. This new insight could inform the development of new combination therapies that will give more cancer patients access to immunotherapy.
The findings have been published in Cancer Discovery.
The protein p53 reacts to damage to cellular DNA and is thought to play a key role in preventing tumour growth. Half of all tumours have mutations in the gene that codes for the protein, and in many other tumours, p53 is disabled by another protein, MDM2.
Previous research has indicated that p53 is able to silence certain sequences in our genome called endogenous retroviruses, therefore preventing genome instability. This new research shows that that the protein can also activate these sequences in cancer cells, leading to anti-tumour immune response.
Lead investigator Galina Selivanova, Professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet, said: “This was an astonishing discovery. When we blocked the suppressor MDM2, p53 activated endogenous retroviruses which induced antiviral response and boosted the production of immune-activating interferons.”
Using mouse models, the researchers blocked MDM2 using a substance coded as ALRN-6924 from the US company Aileron Therapeutics. The increase of interferon response was also seen in tumour samples from two patients taking part in the company’s clinical trials of ALRN-6924.
Combination therapy
Professor Selivanova continued: “This shows that there are synergies that should be exploited between substances that block MDM2 and modern immunotherapies.
“A combination of these can be particularly important for patients who don’t respond to immunotherapy.”
Current barriers to immunotherapy
Immunotherapy is a type of cancer treatment that boosts the body’s natural defences to fight cancer cells. It is thought of as a revolution in modern cancer treatment, but it does not work for all patients, and the presence of interferons could be a biomarker for whether immunotherapy will prove efficacious.
Professor Selivanova is a pioneer in research on how mutated p53 can be re-activated using special molecules. One of these, APR-246, is currently undergoing clinical studies under the name Eprenetapopt at Aprea Therapeutics, a company that she co-founded.
“If we can increase the level of interferons, we can therefore increase the chances that the immunotherapy will succeed.
“We now want to examine if Eprenetapopt produces the same interferon boost and can have the same potential to increase access to immunotherapy for patients with severe forms of cancer,” added Professor Selivanova.
