NEW YORK – Early yet encouraging Phase I/II data presented during the European Society for Medical Oncology Congress on Friday demonstrated that TCR2 Therapeutics' autologous cell therapy, gavocabtagene autoleucel, could shrink tumors across a variety of mesothelin-expressing solid tumor types.
The technology behind the treatment, dubbed gavo-cel for short, involves harvesting patients' T cells and engineering them using a lentiviral vector that encodes the genetic information needed to turn them to T-cell receptor fusion construct T cells, or TRuC-T cells. These engineered cells are designed to recognize and kill tumors by targeting an antigen on the cancer cell surface, in this case mesothelin. After a lymphodepleting chemotherapy regimen, patients receive the engineered TRuC-T cells as a one-time infusion.
During a presentation at the meeting of a Phase I dose-escalation study involving gavo-cel, David Hong, deputy chair of MD Anderson Cancer Center's department of investigational cancer therapeutics, explained that one of the reasons that mesothelin was selected as the therapeutic target is that it is seldom expressed on healthy, noncancerous tissues. On various cancer tissues, on the other hand, mesothelin is highly expressed and associated with poor prognosis due to its role in promoting tumor growth and metastasis.
"This differential expression makes mesothelin an attractive candidate for targeted therapy," he said, explaining that targeting mesothelin could minimize on-target, off-tumor toxicities. He also pointed out that gavo-cel is engineered to recognize tumor surface mesothelin in a human leukocyte antigen (HLA)-independent manner, meaning that patients with high mesothelin expression on their tumors could potentially benefit from the treatment irrespective of the specific HLA subtype.
"This feature of our platform has ensured that we have a surplus of patients waiting to be treated in the Phase II portion of the trial," TCR2 CEO Garry Menzel said in a call with investors following the ESMO data presentation. "[There is] a broad opportunity for us to bring gavo-cel to cancer patients in multiple solid tumor indications."
Patients enrolled in gavo-cel's Phase I/II trial were required to express mesothelin on more than 50 percent of their tumor cells as determined by immunohistochemistry. The types of solid tumors eligible for this trial included malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, and non-small cell lung cancer.
As of the June cutoff date for the data presented during the meeting, 17 patients — 12 with mesothelioma, four with ovarian cancer, and one with cholangiocarcinoma — had received gavo-cel infusions in the study's dose-escalation portion. The patients had been heavily treated before enrolling in the trial.
Out of 16 patients evaluable for treatment efficacy, 15 experienced tumor shrinkage following gavo-cel, though there was a wide range in terms of the magnitude of tumor reduction, ranging from 5 percent to 75 percent. Six patients achieved partial responses according to RECIST criteria, one of whom was considered to have had a complete metabolic response. The one patient with cholangiocarcinoma also had a partial response. An independent review team determined that the overall response rate was 25 percent, and the disease control rate was 81 percent.
Although the main goal of the first phase of the trial was to determine gavo-cel's recommended Phase II dose and chart its efficacy according to overall response rate, Hong also shared some preliminary survival data. Among mesothelioma patients, who made up the majority of the small patient cohort, the median overall survival was 11.2 months, and the median progression-free survival was 5.9 months.
Hong noted that the toxicity profile of the treatment remained manageable, although dose-limiting toxicities did occur when investigators upped the gavo-cel dose, leading them to set the maximum tolerated dose at 5x108/m2.
Given these preliminary survival results, Alfonso Quintas-Cardama, TCR2's chief medical officer, said during the call with investors that "the data we have generated so far reinforce our confidence in being able to pursue a registrational path in this [mesothelioma] indication." The US Food and Drug Administration recently granted orphan drug designation to gavo-cel for the mesothelin-expressing cholangiocarcinoma patient population.
Quintas-Cardama, who called the survival data "highly encouraging," pointed out that this Phase I/II trial involved patients who had undergone extensive prior therapy, but the survival data compared favorably to the survival times patients experienced with second-line treatment approaches following initial upfront chemotherapy.
BMS's combination immunotherapy, ipilimumab (Yervoy) plus nivolumab (Opdivo), of note, was approved last year for upfront mesothelioma treatment, so it remains to be seen how the gavo-cel data will compare to not-yet-reported outcomes that immunotherapy-refractory patients experience on second-line chemotherapy. "Gavo-cel may be highly competitive for the treatment of patients with mesothelioma who have failed standard therapy," Quintas-Cardama said, adding that the treatment is also "poised to deliver on its broad applicability beyond these tested indications."
As the ongoing gavo-cel trial continues into its Phase II portion, TCR2 has decided based on Phase I data to incorporate a lymphodepleting chemotherapy regimen for all patients. Specifically, Hong noted in his presentation that patients in the first portion of the trial who had not undergone lymphodepletion prior to gavo-cel infusion still experienced tumor regression, but the magnitude of these responses was far greater among those who did undergo lymphodepletion. Peak gavo-cel expansion was also higher among patients following lymphodepletion.
In the Phase II portion, TCR2 will evaluate gavo-cel both as a monotherapy and in combination with anti-PD-1 immunotherapy agents, explore the potential effects of retreatment with gavo-cel, and experiment with lowering the mesothelin cutoff so more patients may be eligible for treatment.