By Tiffany Yesavage, PhD

By no means should cyborgs be disparaged—even if they are very small. For instance, the cellular cyborgs that serve as living drugs should be accorded the utmost respect. The U.S. Food and Drug Administration (FDA) certainly thinks so. Since 2017, the agency has approved multiple cellular cyborgs—more commonly known as chimeric antigen receptor (CAR) T-cell therapies—for various blood cancers.

In these therapies, the patient’s own T cells are collected and genetically engineered so that they produce an artificial protein—the CAR—that will target specific antigens found on cancer cells. Once the cells are engineered, they are infused back into the patient.

Unlike the all-but-unstoppable cyborgs of science fiction, CAR T cells are, well, stoppable. For example, they have struggled against solid tumors. Consequently, some therapeutic developers have been exploring alternatives to CAR T cells. One such company is Alloplex Biotherapeutics. It claims to have a highly differentiated, nonengineered, cellular therapy platform with potentially broad antitumor activity across multiple tumor types.

SUPLEXA cells
Alloplex Biotherpeutics has developed a highly differentiated, nonengineered, cellular therapy platform. It produces SUPLEXA cells, which offer potentially broad antitumor activity across multiple tumor types. Left: A low-magnification view of SUPLEXA cells growing vigorously as large multicell clusters. Cells typically expand over 1,000-fold during standard manufacturing timelines. Right: A high-magnification view of SUPLEXA cells shows the characteristic oblong shape of an activated immune cell. Pseudopods at the lower left of the central cell suggest a high potential for mobility in the body.

“The CAR T-cell approach has been phenomenal and has opened the door to a new therapeutic modality,” says Frank Borriello, MD, PhD, the company’s scientific founder and CEO. “However, the first entrant into any field is rarely the optimal solution.”

Borriello explains that the search for cell therapies has prompted some to reconsider the cyborgian approach. “Do we engineer or not engineer?” he asks. “The original CAR T cells were engineered to specifically recognize tumor cells.”

Whether or not cyborgian or more naturalistic cell therapies are deployed, another question looms. Should cells be obtained from patients or healthy donors? (The former approach results in autologous treatments; the latter, allogeneic treatments.) Whereas the original CAR T-cell approach used a patient’s own cells, various allogeneic treatments are being pioneered.

three domains of Triumvira’s T-cell antigen couplers (or TACs)
Triumvira Immunologics is developing targeted autologous and allogeneic T-cell therapeutics that co-opt the natural biology of T cells to treat a broad range of patients with cancer. This schematic shows the three domains of Triumvira’s T-cell antigen couplers (or TACs). The DC4 co-receptor domain, unique to Triumvira’s technology, anchors the TAC in the cell membrane and can either activate or silence the T cell.

Questions about engineering options and cell sources—and other subjects—are discussed by the experts quoted in this article. Besides insights from Alloplex’s Borriello, this article includes insights from representatives of Atara Biotherapeutics, Iovance Biotherapeutics, and Triumvira Immunologics. All of these companies are exploring innovative cell therapies, including therapies that harness diverse cell types, minimize side effects, and offer the potential to target solid tumors.

Retraining immune cells without engineering

Borriello had 25 years of experience in the pharmaceutical industry when two major events changed his life. First, he lost his brother to colorectal cancer. Then, he received a generous severance package. “So, I did something more entrepreneurial than I had ever done before,” he says, “I started a company.”

Borriello established Alloplex to develop what he calls SUPLEXA therapeutic cells. He stresses that, unlike CAR T cells, SUPLEXA cells are not genetically engineered. “They work just like normal immune cells—but in a more robust way,” he asserts. “In clinical trials, we’ve observed profound effects without toxicities.”

Borriello explains that the SUPLEXA procedure begins with a simple blood draw, after which white blood cells are isolated and taken through a proprietary manufacturing process, one that involves Alloplex’s engineered leukocyte stimulator cells (ENLIST cells), which serve as training cells.

Alloplex indicates that ENLIST cells engage multiple activating receptors on various peripheral blood mononuclear cell (PBMC) subsets to enhance direct antitumor activity. The resulting PBMC-derived trained cells are the SUPLEXA cells. They emerge following co-incubation with ENLIST cells without any additional engineering steps.

SUPLEXA cells are comprised of immune cells that are at a heightened state of activation as determined by high-level expression of adhesion molecules, chemokine receptors, activation receptors, and granzymes. This array of proteins enables both direct tumor lysis and antigen presentation to host immune cells. These effects further amplify the host antitumor response.

“We describe our treated cells as highly activated to kill cancer cells directly,” Borriello remarks. He emphasizes that a major advantage of SUPLEXA cells is their capacity for multiple mechanisms of action. To begin with, the cells acquire the ability to recognize and kill tumors. They also train the host’s T cells to recognize and kill tumors by scavenging and displaying tumor cell fragments. “Finally,” he points out, “SUPLEXA cells express specialized homing receptors that allow them to migrate to the bone marrow and favor an antitumor immune response.”

Borriello is optimistic about Alloplex’s future and tells the remarkable story of a woman in her early sixties with advanced metastatic colorectal cancer. “She had exhausted all standard options and had lost hope,” he relates. However, within six months of treatment with SUPLEXA cells, the tumor started to get smaller, and she is now reported to be in complete remission—with no sign of cancer detected on scans.

Pioneering allogeneic approaches

Atara Biotherapeutics, a developer of allogeneic T-cell immunotherapies, has been targeting difficult-to-treat Epstein-Barr virus (EBV)-driven conditions. “Our technology,” states Alexander Chapman, the company’s head of corporate communications and investor relations, “is based on leveraging our body’s natural, evolutionarily honed immune response to EBV.”

EBV is best known for causing mononucleosis. In people who have a weakened immune system, EBV can do far worse. It can elevate the risk for certain cancers and multiple sclerosis.

Atara’s allogeneic platform selects preexisting T cells that already recognize EBV proteins. Once infused into the patient, these activated cells retain their natural ability to target EBV-infected cells and fight the root cause of disease throughout the body.

Atara is focusing on allogeneic treatments. “The allogeneic approach—which does not have to be custom-designed for each patient—is ideal for scalability to produce large quantities,” Chapman says. “Our products can be stored and made readily available for off-the-shelf treatment within days.”

Chapman notes that many allogeneic treatments can lead to graft vs. host disease in which donor cells are identified as foreign, resulting in host-mediated rejection. He adds a caveat, however: “Our EBV-activated cells recognize only very specific viral antigens, leading to low reactivity and minimal side effects following infusions.”

Atara’s pipeline spans preclinical development to commercialized products. Notably, the European Medicines Agency approved Atara’s Ebvallo (tabelecleucel), a first-in-class allogeneic T-cell therapy for EBV-positive post-transplant lymphoproliferative disease.

After disappointing results from a Phase II study of ATA188, Atara’s allogeneic T-cell immunotherapy for progressive multiple sclerosis, the company indicated that it maintains a “strong conviction” in the potential of its pipeline. Atara added that it was looking forward to upcoming milestones, including preclinical data for ATA3431 (a CD19-CD20 CAR T-cell candidate) and clinical data for ATA3219 (a CD19 CAR T-cell candidate). Phase I results are expected in the second half of 2024 for ATA3219 against relapsed/refractory B-cell non-Hodgkin’s lymphoma. Atara also plans to expand ATA3219 development into autoimmune disease.

Reinvigorating tumor-infiltrating lymphocytes

Brian Gastman, MD, is the executive vice president of medical affairs at Iovance Biotherapeutics, and Jim Ziegler is the company’s commercial executive vice president. They provided a joint statement explaining that tumor-infiltrating lymphocytes, called TILs, are naturally occurring immune cells that recognize and kill cancer cells. They added, however, that “once cancer invades the immune system, TILs lose their ability to perform their intended function.”

One of the limitations of CAR T cells is that they act only on a few shared antigen targets common to many tumors. “Most solid tumors are made up of diverse, patient-specific antigens, with only 1% being shared among patients,” Gastman and Ziegler noted. “To access these patient-specific antigens, our process collects TILs from each patient’s tumor.”

Over 22 days, these cells are amplified and reinvigorated outside the body using the company’s proprietary Gen 2 process. The TIL therapy is then cryopreserved, and samples are infused back into the patient. “Inside the body, billions of reinvigorated TILs are deployed,” the colleagues added. “They recognize tumor markers specific to the patient’s own cancer cells.”

Iovance is performing clinical trials for multiple advanced solid tumor cancers, including melanoma, non-small cell lung cancer (NCSLC), and cervical cancer. For instance, for NCSLC, the company has three studies investigating multiple treatment regimens at various stages of the disease. The company is also conducting a Phase II trial for cervical cancer.

Finally, Iovance is testing a TIL treatment called lifileucel in advanced melanoma. A randomized Phase III trial of lifileucel (compared with pembrolizumab immunotherapy alone) is underway in patients with unresectable or metastatic melanoma without prior systemic treatment. Gastman and Ziegler indicated that the company hopes to “deliver lifileucel as the first individualized, one-time cell therapy for a solid tumor.”

Genetic engineering with less toxicity

Triumvira Immunologics asserts that it is developing “non–gene edited, first-in-class targeted autologous and allogeneic T-cell therapeutics that co-opt the natural biology of T cells to treat patients with solid tumors.” Triumvira’s CEO, Paul Lammers, MD, asserts that the company’s technology “is showing great promise in preclinical studies and early clinical data.”

Lammers says that Triumvira’s platform involves the addition of a unique co-receptor that works alongside T cells to prevent toxicity. These internal co-receptors, called T-cell antigen couplers, or TACs, help to transmit signals into the cell. “Think of it as activating the T cells when needed,” he explains. “It is like flipping on a switch when you really need them but then turning them off before they cause harm.”

Lammers notes that conventional immune system–boosting CAR T-cell therapies tend to have high toxicity, which limits their utility against solid tumors. “In contrast,” he stresses, “our TAC technology taps into the natural power of T cells, helping them recognize and attack cancer cells without causing as much harm to healthy tissue.”

Lammers also highlights that Triumvira is leveraging both autologous and allogeneic treatments: “We see benefits to both approaches. Autologous treatments are customized for each patient, which can be time-consuming and costly. On the other hand, allogeneic treatments are more readily available but require careful matching to avoid complications.”

Lammers notes that Triumvira’s TACs are being tailored to treat a wide variety of solid tumors. Current targets include HER2, claudin-18.2, GPC3, and GUCY2C. Last June, preliminary findings from a Phase I/II study (TACTIC-2) indicated that TAC01-HER2, Triumvira’s autologous therapy designed to target relapsed or refractory HER2-positive gastric and gastroesophageal junction tumors, achieved a 67% disease control rate in heavily pretreated patients, including those who had exhausted all standard-of-care therapies. The results also indicated acceptable and manageable safety profiles. Then, in October, Triumvira announced that the first patient had been dosed in Phase II of the study.

“Our goal,” Lammers states, “is to develop a more sparing regimen for cancer patients in the third line of treatment and beyond.”

The future of immune cell therapy

Borriello emphasizes the importance of working with the immune system’s natural ability to recognize and kill tumor cells. “For the most part, our immune systems work well,” he points out. “Most people live their entire lives without ever getting cancer. In the future, I expect to see more focus on approaches that work harmoniously with the body to fight cancer more naturally and without toxicities.”

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