Initial data from ongoing studies of two T-cell receptor (TCR) programs presented by Adaptimmune Therapeutics plc at the European Society for Medical Oncology 2018 Congress showed what Rafael Amado, the company's president of R&D, called encouraging safety, "dose appropriate persistence and expansion, and early but transient evidence of antitumor activity in one ovarian cancer patient."

The trials are testing Adaptimmune's wholly owned MAGE-A10 and MAGE-A4, TCRs from the company's SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform. Adaptimmune gained early validation of the platform when Glaxosmithkline plc moved faster than expected to ink an exclusive license another SPEAR program, NY-ESO, in synovial sarcoma about a year ago. (See BioWorld, Sept. 8, 2017.)

Though experience from the NY-ESO program suggested that the benefits of the TCR therapy may become evident only at higher cell doses than those reported so far for MAGE-A10 and MAGE-A4, some investors weren't waiting for good news Monday, sending company shares (NASDAQ:ADAP) down 29.8 percent to close at $7.55.

"I think expectations in cell therapy are that everything works all the time and everything short of that is seen as flawed," Adaptimmune CEO James Noble told BioWorld. Making clear that the modality is not so straightforward, Noble indicated that Adaptimmune is learning about how to achieve the best results as it goes.

MAGE-A10 is being tested in patients with non-small-cell lung cancer (NSCLC) in one cohort and, in another cohort, bladder, melanoma and head and neck cancers. MAGE-A4, by contrast, is being evaluated in a "basket" study in NSCLC, bladder, melanoma, synovial sarcoma, myxoid/round cell liposarcoma, head and neck, ovarian, gastric and esophageal cancers.

"What we're learning from cell therapy in solid tumors is that they're quite sensitive to the preconditioning regimen and the dose," Noble said. Without good in vivo expansion, the cells won't affect the tumor, he said, noting that with some of the tumors in the studies reported, the preconditioning wasn't strong enough. To improve potential response, investigators are adding a day of fludarabine preconditioning in the third cohort of the study and quintupled the dose. "The third cohort is really where you're giving the cells a chance," Noble said.

Third cohort dosing in the MAGE-A10 study began in July, following favorable safety data from the second dose cohort of patients who received 1 billion transduced SPEAR T cells targeting MAGE-A10 in the NSCLC study, as well as those who had received 100 million cells in the first cohort. In the third cohort, patients will receive 1.2 billion to 6 billion cells to evaluate safety, including dose-limiting toxicities. If there are none, investigators will then move to an expansion cohort, in which they'll treat patients with doses of up to 10 billion cells.

Third cohort dosing in the MAGE-A4 study began in August, the company reported, with a similar dose-escalation plan, featuring between 1.2 billion and 6 billion cells, as compared to 100 million MAGE-A4 T cells each for patients in the first dose cohort and 1 billion cells each for patients in the second cohort of that study.

Initial data from cohort three from both studies are expected to come out around the time of the J.P. Morgan Healthcare meeting in January, followed by more substantial data around the end of the first quarter, Noble added.

On the safety front, the company said the most frequent adverse events (AEs) and treatment-related AEs "are consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies."

Though decreasing his estimate of the programs' probabilities of success to 25 percent from an earlier 35 percent, Raymond James analyst Reni Benjamin said that both programs "continue to showcase a good safety profile with lower rates of cytokine release syndrome as compared to the CAR T space."