Alexander M. Castellino, PhD

June 18, 2015

Chimeric antigen-receptor (CAR) T-cell therapy has repeatedly provided dramatic results in patients with hematologic malignancies.

Now comes the first success story of CAR T-cell therapy in a solid tumor — pancreatic cancer. Results were reported at the American Society of Clinical Oncology 2015 Annual Meeting in Chicago.

It is too early to tell if this approach can replicate, for example, the impressive 70% complete response rates reported in patients with acute lymphoblastic leukemia or non-Hodgkin's lymphoma, which were recently published (Lancet.  2015;385:517-528),  as reported by Medscape Medical News.

But the first hurdle in solid tumors — a proof-of-concept study — has been overcome.

Investigators from the University of Pennsylvania in Philadelphia successfully manufactured and infused appropriate CAR T-cells against pancreatic cancers in six patients with refractory disease, with some metastatic lesions disappearing in one patient.

Four patients showed progressive disease and two had stable disease — for 3.7 and 5.3 months. Stable or decreased metabolic activity in the tumors of four patients was also seen. Significantly, the specially adapted T-cells used in this study, known as CARTmeso cells, were shown to traffic to tumor sites in patients.

The investigators indicate that manufacturing CARTmeso cells against pancreatic cancer is feasible and safe, said presenter Gregory L. Beatty, MD, PhD, assistant professor of medicine at Penn, which has been on the cutting edge of the development and clinical application of the technology.

 
Promising clinical and radiologic signs...were seen, but were transient.
 

"Promising clinical and radiologic signs suggestive of antitumor activity were seen, but were transient," Dr Beatty explained.

But the CAR technology alone might not be enough in this setting, he acknowledged. Combination therapies to enhance the persistent and prolonged effector activity of CARTmeso cells are needed, Dr Beatty said.

CAR T-Cells in Pancreatic Cancer

CARs have a target-recognition end, which is usually the antigen-recognition domain of an antibody (the V region), and a "business" end, which activates T-cells. The failure of CAR technology in solid tumors has been attributed to the failure to identify potential targets on tumor cells, said Dr Beatty

In the past, CARs were directed against self proteins, which are also present on normal cells, resulting in on-target, off-tumor toxicities, he reported.

In this study, the investigators took advantage of the fact that mesothelin, a membrane-anchored protein normally seen in mesothelial cells, is overexpressed in all pancreatic cancer tissue examined so far.

Dr Beatty and his colleagues engineered a second-generation CAR with the antibody-binding region to mesothelin fused with the signaling domain of a T-cell receptor and a costimulatory molecule, 4-1BB (CARmeso).

Manufacturing CARTmeso Cells

Manufacturing T-cells expressing CARmeso (CARTmeso cells) was done on an individual patient basis and occurred over 28 days. Patients' white blood cells were collected with apheresis, and the lymphocytes were then separated and expanded using established protocols.

CARTmeso cells were manufactured using one of two platforms: an RNA platform, which allows for a transient expression; or lentivirus, which integrates into the DNA of the T-cells and allows for the  permanent expression of CARmeso. The CARTmeso cells were then infused back into the patient.

Baseline imaging and tumor biopsy were performed concurrent to the manufacturing of CARTmeso.

Patients with treatment-refractory pancreatic cancer were provided with three weekly infusion of CARTmeso cells 1 to 3 × 10⁸/m² using the RNA platform.

Dr Beatty reported that CARTmeso cells were successfully manufactured in 85% of patients, and 53 of the 54 planned infusions were administered. Average time from screening to treatment took 41 days.

Six patients received CARTmeso cells. Dysgeusia, abdominal pain, and fatigue were commonly reported adverse events. On-target, off-tumor toxicity was not observed, and cytokine-release syndrome was not a serious adverse event.

Dr Beatty reported that a study with the lentiviral platform is planned.

In addition, protocols are in place for targeting mesothelin in mesothelioma and ovarian cancer, both of which overexpress mesothelin, said Carl H. June, MD, from Penn, in  an interview posted on the Cancer Research Institute website.

Mesothelin overexpression has been observed in triple-negative breast cancer and in lung cancer, where the feasibility of CART technology will also be explored.

The University of Pennsylvania is not the only group working on CARs for solid tumors. For example, Seattle-based Juno Therapeutics has four product candidates that have solid tumor targets, and studies will be initiated in the next 12 to 18 months.

Juno is working with the Fred Hutchinson Cancer Research Center, also in Seattle, the Memorial Sloan Kettering Cancer Center in New York City, and other institutions, and will be testing its first "armored" CARs, a technology platform that attempts to overcome the immune modulatory effects of cancer.

"We believe this technology will be especially useful in solid tumor indications, in which microenvironment and potent immunosuppressive mechanisms have the potential to make the establishment of a robust antitumor response more challenging. Juno's strategy will also include intensively interrogating the tumor microenvironment and to better understand the pathways that we may need to modulate in order to optimize efficacy in solid tumors," according to a company statement sent to Medscape Medical News.

The study was supported by the Cancer Research Institute and Lustgarten. Dr Beatty reports ties with industry.

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