Research

Bispecific antibody offers CTLA-4 blockade without the toxicity


A/Prof Ben Tran

A first-in-human trial of a monovalent bispecific antibody targeting PD-1 and CTLA-4 has found encouraging antitumour activity in patients with advanced solid tumours but without the typical toxicity of high dose CTLA-4 blockade.

The phase I, open-label, international study presented at the 2022 AACR Annual Meeting, enrolled 86 adults with hard to treat cancers including RCC (22.1%), NSCLC (16.3%), and head and neck cancer (8.1%). Most patients (95.2%) had received prior systemic therapy and most (90.7%) were immunotherapy-naïve.

Patients were treated at dose levels from 2.25-2500 mg IV Q3W until progression or unacceptable toxicity.

Lead investigator Associate Professor Ben Tran from the Peter MacCallum Cancer Centre, told the limbic that the background to the study was that high doses of anti-CTLA-4 agents such as ipilimumab and tremelimumab can improve survival.

“But despite this increased survival, the high doses have not been adopted because of the toxicity. The challenge for us as researchers is to find a way to develop new therapies that block CTLA-4 in a more significant way and therefore improve survival without causing an increase in toxicity.”

“So MEDI5752 is a monovalent, bispecific antibody that targets both PD-1 and CTLA-4, and is designed to enhance the blockade of CTLA-4 but preferentially on the PD-1 positive activated T cells. As such, it is a possible engineering solution to overcome the toxicity that limits the ability to deliver higher doses of anti-CTLA-4.”

Associate Professor Tran said the study had shown that they could achieve blockage of CTLA-4, that is similar to the very high doses of ipilimumab or tremilimumab, but without the side effects.

“In particular, colitis which is very common with anti-CTLA-4 therapies was very uncommon in our trial,” he said.

He said the study offered a proof of concept that the bispecific approach was able to do what it was designed to do – deliver a higher blockade of CTLA-4 in combination with a PD-1 blockade.

The study demonstrated both peripheral T cell proliferation and T cell activation.

“That is what it’s supposed to do. If we have shown we are causing T cell clonal expansion but a lot of them are new clones, that means the drug is inviting the immune system to fight something it hasn’t fought before and hopefully that is the cancer.”

An objective response was seen in 19.8% of patients across all doses and the median duration of response was 17.5 months.

Associate Professor Tran said the team were currently completing dose expansion studies. Data in kidney cancer will be presented at the 2022 ASCO Annual Meeting.

MEDI5752 is developed by AstraZeneca.

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