Nature Medicine: Novel T-cell receptor therapies show early anti-tumor activity

Afamitresgene autoleucel (formerly ADP-A2M4, abbreviated afami-cel) is an adoptive T cell receptor (TCR) therapy targeting the MAGE-A4 cancer antigen that has achieved significant clinical efficacy
in patients with multiple solid tumor types in a Phase I clinical trial led by researchers at the University of Texas MD Anderson Cancer Center.

Clinical results published in the journal Nature Medicine are particularly noteworthy in the subgroup of synovial sarcoma patients, where afami-cel achieved an objective response rate of 44 percent, compared to an overall response rate of 24 percent
for all cancer types.
Preliminary data from this trial were presented
at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

Lead researcher David S.
Hong, Ph.
D.
, said these early results demonstrate a proof-of-concept
for this novel cell therapy approach in solid tumors.

"These high response rates are very important because synovial sarcoma patients really have few options
after receiving high-dose chemotherapy for ifosfamide," Hong said.
The overall toxicity of afami-cel is manageable, and we see evidence
of early activity in other cancer types.
These results suggest that this is an approach that has the potential to play a role in solid tumors, where there are currently no approved cell therapies
.
”

The goal of TCR therapy is to more accurately target solid tumor cells without the toxicity
to normal cells typically associated with chimeric antigen receptor (CAR)-based cell therapies.
Unlike CAR-based cell therapies that recognize specified surface proteins, TCR therapies like afami-cel can target proteins
normally found inside cells.
Using the native receptors of T cells, TCR therapy can recognize protein fragments that bind to cell surface immune-associated proteins (in this case from MAGE-A4).

In this study, a total of 38 patients were treated with AFAMI-CEL, with an average of 3 treatment options
.
58% of the participants were men; 92% of the participants were white, the rest were Asian
.
The study included 16 patients with synovial sarcoma, 9 patients with ovarian cancer, 3 patients with head and neck cancer, esophageal cancer, non-small cell lung cancer, urothelial carcinoma and muxoid/round cell liposarcoma, and 1 patient each with gastric cancer and melanoma
.

All patients experienced treatment-related adverse events, with low blood counts (lymphopenia, leukopenia, neutropenia, anaemia, and thrombocytopenia) being the most common
.
Seventeen patients (45%) experienced persistent cytopenia
4 weeks after AFAMI-CEL treatment.
Two patients developed trial-related deaths, resulting in a lower maximum age for screening and discontinuation of high-dose cyclophosphamide lymphatic failure regimens
.

The median time to response was 26 weeks for all patients and 28 weeks
for the synovial sarcoma subgroup.
These results in synovial sarcoma led to an ongoing phase II trial of afami-cel in patients with advanced synovial sarcoma or mucinoid/round cell liposarcoma, also led
by MD Anderson.

The early results of afami-cel also led to another phase I trial, also led by Hong, evaluating the next generation of afami-cel, the ADP-A2M4CD8
.
This new TCR therapy expresses the CD8 co-receptor and is designed to amplify the immune response
in solid tumors.
Hong shared encouraging early data
from the trial at the 2022 European Society of Medical Oncology (ESMO) Congress.

The trials are part of an ongoing strategic alliance between MD Anderson and Adaptimmune to accelerate the development of
novel T-cell therapies for multiple cancer types.