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HomeOncologyPromising ‘killer’ cancer treatment targets hard-to-treat tumours – UK trial

Promising ‘killer’ cancer treatment targets hard-to-treat tumours – UK trial

Researchers at the Institute of Cancer Research (ICR), London, and the Royal Marsden NHS Foundation Trust who have been trialling the new drug, known as AFM24, said that it was able to target the cancer protein without redeveloping the cells of the patient.

According to results of phase 1 of the ongoing trial, out of the 24 patients, eight saw their cancers stop growing. The trial involved patients with tumours containing a key protein in cancer growth known as Epidermal Growth Factor Receptor (EFGR).

The treatment showed signs of effectiveness in a third of the patients who had a range of advanced cancers that had stopped responding to treatment, including bowel, lung and pancreatic cancers.

AFM24 redirects the body’s own natural killer immune cells to kill tumour cells, without having to go through the complex process of re-engineering a patient’s own cells, known as CAR-T cell therapy.

Experts hope the immunotherapy could, in future, work against a range of cancer tumours that continue to grow despite treatment. They also believe the new treatment has the potential to be safer and less complex than cell therapies like CAR-T, and might work against a wider range of cancer types.

The trial has been funded by the drug’s manufacturer Affimed N.V. and is testing the drug’s safety and what dose should be given, as well as its effectiveness in tackling tumours positive for EGFR – a key protein involved in cancer growth.

Two patients with bowel cancer and one with lung cancer who received the immunotherapy saw their cancer shrink or stop growing for more than three months.

AFM24, which is administered intravenously, was generally well-tolerated by patients.

The ICR said the immunotherapy has a “warhead” targeted at EGFR, which is commonly produced by lung, bowel, kidney, stomach, pancreatic and biliary cancers.

Further studies are now evaluating AFM24 in combination with other immunotherapies such as atezolizumab to target EGFR-positive tumours.

The trial’s UK lead Dr Juanita Lopez, from the ICR and consultant medical oncologist at the Royal Marsden, said: “Natural killer cells are an essential part of the immune system and are able to recognise cancer cells.

“This new immunotherapy, AFM24, can redirect natural killer cells to tumours by targeting a protein called EGFR, which is often found on the surface of cancer cells. The treatment is still highly experimental and our trial is at an early stage, but we are excited by its potential. It does not have to be personalised for each patient like CAR-T cell therapy, so it could potentially be cheaper and faster to use, and might work against a wider range of cancers.”

Professor Kristian Helin, chief executive of the ICR, said: “This treatment is highly innovative because it finds a way to direct natural killer cells within the immune system to tumours without requiring complex and expensive re-engineering of a patient’s own cells.

“So far, we’ve only seen initial findings in a small group of patients, but the results look promising, and we’re optimistic that this could be a new type of immunotherapy for cancers that are otherwise hard to treat.”

The findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 in New Orleans on 12 April 2022.

Study details

CT149 / 16 – A phase 1/2a first-in-human study of AFM24, a CD16A/epidermal growth factor (EGFR) bispecific Innate Cell Engager (ICE®), in patients with locally advanced or metastatic EGFR expressing solid tumors: Preliminary findings from the dose-escalation phase

Anthony El-Khoueiry, Juanita Lopez, Omar Saavedra, Mark Awad, Jacob Thomas, Crescens Tiu, Elena Garralda, Bettina Rehbein, Gabriele Hintzen, Kerstin Pietzko, Christa Raab, Erich Rajkovic, Paulien Ravenstijn, Michael Emig.

Abstract

AFM24 is a first-in-class, tetravalent, bispecific ICE® that binds to EGFR on tumour cells and CD16A on natural killer (NK) cells and macrophages, inducing antibody mediated cytotoxicity and antibody-mediated phagocytosis, respectively. Preclinical in vitro and in vivo studies have demonstrated AFM24 can induce killing of EGFR+ solid tumour cell lines, independently of EGFR mutational status; toxicology testing in cynomolgus monkeys revealed a favourable safety profile.

An ongoing phase 1/2a study (NCT04259450) is evaluating the safety, efficacy, immunogenicity, pharmacokinetic (PK) and pharmacodynamic responses of AFM24 in patients with locally advanced or metastatic, treatment refractory solid tumours that are known to express EGFR. AFM24 is administered intravenously Q1W until disease progression, intolerable toxicity, investigator’s discretion or patient withdrawal.

As of 29 Oct 2021, 29 patients (median [range] age 58 [29-81] years; number of prior therapies 4 [2-8]), predominantly with colorectal- (CRC, 16/29; 10 KRAS mutant) and non-small cell lung cancer (NSCLC, 7/29; 6 EGFR mutant), were treated with AFM24 across six dose levels (14-480 mg flat). The median number of AFM24 doses administered was 8, range 1-29. The most frequently reported (≥20% of patients) AFM24-related treatment-emergent adverse events (TEAEs) were infusion-related reactions (IRR, 20/29), nausea (7/29) and headache (6/29).

There were no on-study deaths; two patients had serious TEAEs (one Grade 3 IRR and one Grade 2 hypoxia) and five patients had transient and reversible Grade 3-4 TEAEs (two Grade 3 IRRs, one Grade 3 hypertension, three ≥Grade 3 lymphocytopenia) attributed to AFM24, respectively. There was one dose-limiting toxicity at 40 mg (Grade 3 IRR). Best objective response was stable disease in 8/24 response-evaluable patients; three patients had stable disease for ≥4 months (two CRC, one NSCLC). Dose proportional PK between 320 and 480 mg indicated saturation of target-mediated elimination. CD16A receptor occupancy (CD16ARO) on circulating blood cells was correlated with exposure and seemed to level off at 480 mg. Estimated intra-tumoural AFM24 concentrations and CD16ARO were in the range associated with maximum tumour cell killing in vitro. TNF-α, IFN-γ and IL-10 increased over time; other cytokines including IL-6 showed only transient increases.

AFM24 has a well-managed safety profile and shows pharmacodynamic activity at doses of 320-480 mg. In parallel to continued dose escalation, expansion in disease specific cohorts has been launched at 480 mg. Other studies are evaluating AFM24 in combination with atezolizumab, and in combination with autologous NK cells holding the potential to activate the innate immune response to fight EGFR+ cancer.

 

Presentation from AACR 2022 (Open access)

 

International Cancer Research London article – AACR 2022: New 'killer' immunotherapy shows early promise in range of solid tumours (Open access)

 

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