Autolus has initiated two Phase 1/2 trials to test AUTO3, a new CAR T-cell therapy that targets two cancer proteins instead of one. The trials, AMELIA and ALEXANDER, will be testing the approach in B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), respectively.
AUTO3 is the first CAR-T cell therapy designed to target two different surface receptors expressed by tumor cells to enter clinical development.
“Our approach at Autolus is to understand how tumors defend against T-cells and then design and program CAR-T cell products which specifically address those defense and escape mechanisms,” Martin Pule, MD, founder and chief scientific officer of Autolus, said in a press release. “The AUTO3 program seeks to overcome two limitations of current therapies by introducing dual targeting CARs and addressing checkpoint-mediated inhibition.”
Like most CAR T-cell therapies, AUTO3 uses the patient’s immune T-cells. The cells are collected and genetically modified to produce two chimeric antigen receptors (CARs) that recognize the CD19 and CD22 proteins found in both B-cell leukemia and lymphoma cells.
A common resistance mechanism seen in CAR T-cell therapies is the loss of the proteins targeted by the receptors. By targeting two different proteins, AUTO3 is expected to reduce the risk of disease relapse.
“The advent of CD19 CAR-T cell-based therapy is an exciting and revolutionary advancement in the treatment of children with relapsed ALL,” said Persis Amrolia, professor of Transplantation Immunology at Great Ormond Street Hospital, London. “However, in approximately a third of the patients the disease reoccurs by losing CD19 antigen. AUTO3, a dual targeting CAR, addresses this challenge by independently targeting CD19 and CD22 antigen, which has the promise of reducing antigen escape.”
AMELIA (NCT03289455) will be testing AUTO3 in 50 B-ALL patients, aged between 1 and 24 years, with confirmed high risk, relapsed or refractory disease.
ALEXANDER (NCT03287817), also a U.K.-based trial, will be conducted at the University College London Hospitals and The Christie NHS Foundation Trust. It is expected to include 120 adult participants with relapsed DLBCL.
In the Phase 1 parts of AMELIA and ALEXANDER, investigators will evaluate increasing doses of AUTO3 to determine an optimal therapeutic dose to be used in Phase 2. The second part of the studies will further assess the safety and tolerability of AUTO3, and determine its clinical activity in these patient groups.
The ALEXANDER study also is evaluating the effects of AUTO3 in DLBCL when used in combination with the checkpoint inhibitor Keytruda (pembrolizumab).
“The field is looking forward to seeing how patients respond to AUTO3 in clinical trials and whether dual antigen targeting CAR-T cell therapy offers the possibility of deeper initial and more sustained responses,” said Anas Younes, MD, chief of lymphoma service at Memorial Sloan Kettering Cancer Center, New York.