ID: P330
Results from the completed dose-escalation of the alloSHRINK phase I study evaluating the allogeneic NKG2D-based CAR T-cell therapy CYAD-101 in metastatic colorectal cancer patients
Hans Prenen, MD, University Hospital Antwerp (UZ Antwerp), Marika Rasschaert, MD, Alain Hendlisz, MD, Leila Shaza, MD, Erik Alcantar-Orozco, MD, PhD, Emilie Cerf, PhD, Florence Renard, Caroline Lonez, PhD, Anne Flament, Jeroen Dekervel, MD, Eric Van Cutsem, MD, PhD
Background
Current success of chimeric antigen receptor T-cell (CAR-T) therapy in hematological malignancies has been achieved using autologous cell products. Whilst feasible in such relatively small patient populations, delivering an autologous product to large cohorts of patients is likely beyond the current logistical capabilities. In the phase 1 alloSHRINK study, we tested the first-in-class non-gene edited allogeneic CAR T-cell therapy, CYAD-101, administered concurrently with chemotherapy, for the treatment of metastatic colorectal cancer (mCRC). The NKG2D-based CAR of CYAD-101 targets eight ligands present at high frequencies in mCRC, not only on tumor cells but also cells from the tumor microenvironment, and co-express a T-cell receptor (TCR) inhibiting molecule (TIM) that interferes with TCR signaling in an attempt to avoid the main issue of allogeneic T-cell therapy, the graft versus host disease (GvHD).
Methods
The alloSHRINK study (NCT03692429) evaluates the safety and clinical activity of multiple infusions of CYAD-101, administered concurrently with standard of care FOLFOX chemotherapy, in patients with non-resectable mCRC who received prior chemotherapy lines (i.e. rechallenge population). Three dose-levels (DL; 1x10E8, 3x10E8 and 1x10E9 T-cells per infusion) were evaluated through a 3+3 design.
Results
In total 12 patients have been enrolled in the dose escalation segment, now completed (3 at DL1, 3 at DL2 and 6 at DL3). At the time of submission, only data from the first two DLs were available. At DL1 and DL2, there was no report of dose-limiting toxicity (DLT) and no patient experienced Grade = 3 related adverse events (uncleaned database). No clinical evidence of GvHD has been recorded. Best overall response = 3 months include 1 partial response and 3 stable disease over the first 6 patients (DL1 and 2). At DL1 and 2, preliminary data show a dose-dependent effect on the cell kinetics and control of the host-versus-graft response against CYAD-101 cells as evidenced by the similar levels of CYAD-101 engraftment after 2nd and 3rd infusions.
Conclusions
As of August 2019, no GvHD has been observed following infusions of non-gene edited allogeneic CAR T-cells to mCRC patients at the first two DLs, with preliminary signals of clinical activity. The study will have reached protocol-specified endpoints for analysis at the time of presentation and safety, clinical and cell engraftment will be presented. The results from this study, in comparison with a study evaluating the autologous analog of CYAD-101 in mCRC will provide critical information to support the development of CAR-T therapy in solid tumors.