Chimeric antigen receptor (CAR) T cell therapy continues to change the cancer treatment paradigm, with four therapies, to date, approved in the US. While opportunities continue to emerge for new cancer targets, CAR T treatments, up to this point, are, however, associated with some major challenges.
Conventional CAR T cell therapies have shown remarkable responses in patients with Hematologic B cell cancer but they require intensive manufacturing, and their expense has also limited patient access to these novel precision medicines, says Dr Helen Sabzevari, CEO of Precigen.
“How do we make CAR T a commercially viable therapy? If you cannot manufacture at lower costs and you cannot get a CAR T cell therapy to enough patients, this immunotherapy will, unfortunately, be lost,” she told BioPharma-Reporter.
Conventional CAR T cell therapies use lentiviruses to deliver genetic material to the cells, adding a layer of manufacturing complexity. “Lentiviruses are limited in their payload. Secondly, conventional CAR T needs centralized manufacturing, patient cells need to be shipped to a specialized facility, and this process takes anywhere from four to six weeks; moreover, the cost associated with that is in the hundreds of thousands of dollars.”
There are additional challenges associated with allogeneic, off-the-shelf CAR T cell therapy approaches, which rely on donor cells, not patient cells, she said: “The donor cells have to be edited, again this is expensive and there are risks. You can also never fully edit everything out from donor cells, so there can also be allogeneic mismatching.”
Still required in the allogeneic process is the delivery of genetic instructions into these cells, again via lentiviruses. “Then they have to expand those cells. [After all that] you can only bank enough cells for perhaps 100 patients.”
So manufacturing of CAR T cell therapies, autologous and allogeneic, is a bottleneck right now, said the CEO. Furthermore, the CAR T cell therapy platforms that currently exist do not allow redosing of a patient, at any given time. Also, the way cells are expanded in existing approaches results in them becoming activated and ‘exhausted’ - in other words, they have a finite life.
This is one of the biggest issues in terms of treating solid tumors as these 'exhausted’ cells don’t survive long enough to get to solid tumors, she explained. “In hematological cancers, you have a better shot, as immediately these CAR T cells see the tumor in the blood, but in solid tumors that is not the case. The metastases are in the organ, so you need the time for the cells to get there, to expand and activate and basically kill the tumor.”
It is also time consuming to ensure drug homogeneity in current CAR T therapies, remarked Dr Sabzevari.
Ushering in a rapid, streamlined manufacturing process
What is Precigen [formerly Intrexon] doing differently?
“When I joined the company, we asked what it would take to differentiate us from the other platforms, how could we address the issues that the other platforms have. We then went about systemically addressing the various challenges.”
That work paid off, resulting in Precigen having a rapid, streamlined manufacturing process that forgoes the need for large, centralized facilities, while avoiding the limited in vivo life-span of current CAR T cells, she maintains.
Its UltraCAR-T manufacturing requires isolation of the patient’s own T-cells after blood draw, followed by non-viral gene transfer using plasmid DNA at medical centers. The next day, following the gene transfer, UltraCAR-T cells are infused into the patient. They are designed to multiply inside the body to fight the cancer.
The UltraCAR-T cells have been optimized using the company’s UltraVector DNA construction platform to deliver a large multigenic payload at high efficiency. The cells are precision-engineered to produce a homogeneous cell product that simultaneously expresses antigen-specific CAR, a kill switch to improve their safety profile, and mbIL15 genes.
“We have control over the expression of these genes, ensuring uniformity of expression which is important in drug homogeneity later on.
“We also wanted to give a mechanism to these cells so that they can sustain themselves and can last a long time in patients, not just a matter of a week or two weeks.
“You want to also express a safety switch or a kill switch - in case something goes wrong in a patient you can eliminate these cells very rapidly,” said Dr Sabzevari.
Moreover, the inclusion of the gene encoding membrane-bound IL-15 slows the aging of UltraCAR-T cells, which results in superior expansion of cells in vivo, eliminating the need for multiple weeks of expansion in culture, she said.
The company’s UltraPorator, its semi-closed, high-throughput system, is capable of handling the electroporation of billions of T-cells in minutes and further streamlines the UltraCAR-T overnight manufacturing process. “It is unlike any other technology in the field,” said Dr Sabzevari.
The advantage of this non-viral system is that it enables decentralized manufacturing. The process can be done in any cleanroom of a hospital or a cancer center, said the CEO. “There is no expansion of these cells in another facility, there is no shipping and receiving after four to six weeks, and there is a very low-price tag.”
The platform also has the flexibility to generate multiple autologous UltraCAR-Ts for patients; redosing, if needed.
The technologies position the company to tap markets for treating both cancers of the blood and solid tumors, she said.
Clinical validation
Its PRGN-3005 UltraCAR-T is under evaluation in an ongoing Phase 1/1b clinical study for the treatment of advanced, recurrent platinum resistant ovarian, fallopian tube or primary peritoneal cancer.
And its PRGN-3006 UltraCAR-T is currently under clinical evaluation in an ongoing Phase 1/1b trial for the treatment of patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or higher-risk myelodysplastic syndromes (MDS).
“In December, we reported on nine patients from our AML trial and on six patients from our ovarian cancer trial, and we showed really encouraging preliminary findings of expansion, persistence and clinical activity in both,” reported Dr Sabzevari.
Precigen, she said, will continue to provide clinical validation of the UltraCAR-T platform.
Ultimately, the company’s technology, said the CEO, will advance the concept of personalized medicine.