Allogeneic Autologous CAR-T or CAR-NK Therapy on cancer treatment?

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Allogeneic, Autologous CAR-T or CAR-NK Therapy on cancer treatment?

Allogeneic, Autologous CAR-T or CAR-NK Therapy on cancer treatment? The technique used in the clinic involves designing a person’s own immune cells, called T cells, to carry a receptor that directs them to attack tumors.

In 2017, the U.S. Food and Drug Administration (FDA) approved two CAR-T products for the treatment of blood or blood tissue cancers. “This is the most important therapeutic innovation in the field of hematology for a generation,” said Martin Pule, a hematologist at University College London. He said that what was once a “somewhat weird approach” has now become the standard of care for certain cancers.

The first approved treatment was tisagenlecleucel (Kymriah), developed by Novartis Pharmaceuticals in Basel, Switzerland. Its use leads to cancer remission in more than 80% of patients with refractory leukemia [1]. Axicabtagene ciloleucel (Yescarta) was developed by Kite Pharma in Santa Monica, California, and is approved for the treatment of relapsed or drug-resistant large B-cell lymphoma. In a clinical trial, 65% of people did not relapse 12 months after the initial response [2].

However, currently only a small number of people in the United States who can benefit from CAR-T therapy are receiving it. The main reason is that the production of Kymriah and Yescarta are both challenging. Both are autologous therapies, which means they use the person’s own cells. Manufacturing begins with the collection of human blood. The T cells are then separated from the sample and shipped to a centralized manufacturing facility, where they are genetically modified to target proteins on cancer cells. The engineered T cells grow [5] to 10 days, and after passing strict safety and efficacy standards, they are transported back to the hospital and given to the original donor.

This complicated manufacturing process sometimes fails. About 30% of Kymriah lymphoma products do not meet the standards set by the FDA. Even if production goes smoothly, it is a long process. Earlier this year, Neelapu and his colleagues looked at the data of about 300 lymphoma patients in 17 centers in the United States to understand how long it would take to produce Yescarta [3]. He said that the average time from donation to treatment is more than three weeks. For people with rapidly proliferative diseases (such as acute leukemia), the waiting time may be too long. Neelapu estimates that 10% to 15% of patients receiving CAR-T have either died or are unwell, so that they cannot risk receiving treatment when they are ready.

The complexity of CAR-T therapy means that the cost of the therapy can be as high as $350,000, and there are relatively few centers in the United States that can provide this therapy.

Researchers are looking for ways to enable more people to use CAR-T therapy. One possibility is to no longer use a person’s own cells to make therapies, but to design T cells from healthy donors. This allogeneic approach can also be applied to immune system elements other than T cells, such as natural killer (NK) cells. However, the use of donor cells is fraught with rejection issues, leading some people to say that the answer lies in simplifying and automating existing autologous CAR-T manufacturing.

Allogeneic/Autologous CAR-T or CAR-NK Therapy on cancer treatment?

CAR-T Therapy is ready to go?

Proponents of allogeneic CAR-T therapy have seen many benefits. Handling cells for dozens of people instead of one person at a time can reduce manufacturing costs and enable hospitals to keep engineered cells on ice, ready to quickly provide them to those in need. “It’s more like a drug than an autologous cell process,” Grup said. This kind of ready-made CAR-T therapy allows hospitals that cannot extract T cells from human blood to provide it. This procedure is called leukocyte removal and is usually reserved by a bone marrow transplant center.

Due to the suppression of cancer or chemotherapy, the use of T cells from healthy donors can benefit people with defects in their own T cells. “One of the main reasons for recurrence after CAR-T treatment is that the patient’s T cells are dysfunctional during leukocyte removal,” Neelapu said. The allogeneic approach may even lead to more ambitious treatments, including CART cells designed for multiple targets (see “New Approaches to Cell Therapy”). This is more difficult to achieve, but when a person’s survival does not depend on the rapid recovery of one’s own cells, if a batch of T cells fails, the risk of a restart may be more acceptable. “The allogeneic world is more tolerant of unsuccessful manufacturing,” Grup said.

However, the existing CAR-T therapies are not without challenges. One problem is that donor T cells can recognize the body of the person being treated as a foreign body and attack it, causing the potentially fatal graft-versus-host disease (GVHD). The second major problem is that foreign T cells may be eliminated by the human immune system before they attack cancer. According to Grupp’s experience, allogeneic cells “almost universally disappear within three to four weeks,” he said. In contrast, Pule detected autologous T cells in humans after two years or more of infusion.

To improve the endurance of ready-made CAR T cells, Allogene Therapeutics, a biotechnology company in South San Francisco, California, genetically modified CAR T cells to remove a protein called CD52 from their surface. The patients are then given antibodies that help destroy the cells carrying the surface protein, depleting their own white blood cells, which might otherwise kill the engineered CAR T cells. To prevent GVHD, the T cell receptors of engineered cells can be changed to prevent them from attacking human cells.

In May of this year, Allogene reported the encouraging results of a phase I trial of allogeneic CAR T cells in 22 patients with diffuse large B-cell lymphoma or follicular lymphoma (see go.nature.com/ 2fssusw). The tumors of most people shrank, and about 40% of the volunteers responded completely to the treatment. “The overall response rate is about the same as the response rate we see in autologous CAR-T products,” said Neelapu, who led the trial.

He added that the number of CAR T cells expanded and reached a peak in the first 2 weeks and lasted for up to 8 weeks. In addition, there were no signs of GVHD or neurotoxicity. “In terms of safety, it looks better than the currently available FDA-approved products,” he said. Cytokine release syndrome-a common side effect of CAR-T therapy, in which proliferating T cells secrete pro-inflammatory cytokines-is experienced by one-third of people, but it is reversible.

It may be possible to solve cancers other than lymphoma, especially solid tumors, and the endurance required is not in weeks but in months or even years. However, another feature of allogeneic cells is that they can be created in batches, allowing repeated administration if their effects begin to diminish. “Most of the data on solid tumors shows that CAR T cells are depleted after a single injection,” said André Choulika, CEO and founder of Cellectis in Paris, from which Allogene obtained a license for some of the technology. “Re-dosing is part of the allogeneic CAR-T concept.” However, Sadelain pointed out that although there are good reasons for hope for allogeneic methods, they have not yet been clinically validated.

What’s the advantage?

When Pule started using CAR T cells about ten years ago, creating them required two technicians to manipulate the cells in a sealed container. “At the time, it seemed that the allogeneic was the answer,” he recalled. However, in his view, advances in manufacturing processes have made autologous CAR-T therapy a viable default long-term option. T

oday’s closed manufacturing system does not require strict clean room requirements, and because the T cell culture process becomes more automated, it requires less technical personnel input. This automation is accelerating the production of CAR T cells-Novartis is trying to reduce the manufacturing time to two days. “These processes are pieced together by academic researchers to ensure safety and reliability,” Sudran said. “We haven’t seen the impact of industrialization.” Software that automates the large amounts of documentation needed to produce cells for everyone is also emerging.

These developments should also reduce costs. “I would be very surprised if the autotherapy price exceeds US$100,000 to US$150,000 in 5 years,” said Mark Lowdell, a cellular immunotherapist at University College London. Although there is no guarantee that the cost will be reduced, it is not certain that the allogeneic CAR-T will bring considerable savings.

Researchers are still debating the relative safety of allogeneic and autologous CAR T cells. Some critics of off-the-shelf methods believe that the requirement to weaken a person’s immune system makes them vulnerable to viruses. Pule is concerned that repeated dosing may eventually cause the human immune system to respond to the CAR itself. At the same time, other researchers believe that autologous CAR T cells that have existed for many years may fight the body’s immune system. “Once they destroy the tumor cells, they start to attack normal B cells,” Rodell said. The recipient may be immunodeficient for life and requires antibody replacement therapy.

Other methods

As the controversy continues, another cell therapy is attracting people’s attention. It has many advantages of allogeneic CAR-T, but has fewer disadvantages. Instead of using T cells that form part of the adaptive immune system, use NK cells.

NK cells are equipped with receptors on their surface to look for signs of danger or stress that may indicate a tumor or cell infection with a virus. When they find such a cell, NK cells can directly attack it and summon T cells to the scene to help. Moreover, it is crucial that donor NK cells do not cause GVHD because they do not express T cell receptors—eliminating the need for expensive immunosuppression.

Katy Rezvani, an oncologist at MD Anderson Cancer Center, led a trial earlier this year in which NK cells collected from umbilical cord blood were modified with CAR so that they could target the CD19 protein found on certain tumor cells [ 5]. NK cells also express IL-15, which is a cytokine that promotes the proliferation and persistence of NK cells. The resulting CAR NK cells were then given to 11 people with relapsed or treatment-resistant non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Eight people responded to treatment within a month. After about 14 months of follow-up, 7 patients had a complete remission and 1 had a partial improvement.

As the first human trial, Rezvani said she was nervous about the potential toxic effects, especially because inserting the gene encoding IL-15 is a new method. But the volunteers did not experience cytokine release syndrome or neurotoxicity. These cells will stay in the body for at least 12 months-something that many people in the field did not expect. These cells usually disperse quickly after finishing their work. “Before I saw Katy Rezvani’s work at MD Anderson, I really didn’t believe that CAR NK cells were a thing,” Grupp said. “You need cells that can proliferate in the patient’s body to get a successful treatment response, but she has proven that they can do it.” The technology is still in its infancy-Sadelain points out that so far, only about 20 people have been affected. Infused with CAR NK cells-but it is now rapidly expanding.

Some researchers are trying to make CAR NK cells more effective. Editas Medicine, a pharmaceutical company in Cambridge, Massachusetts, is using gene editing technology CRISPR to remove TGF-β receptors on NK cells. TGF-β is a signaling molecule produced by certain tumors that can shut down immune cells. It is hoped that removing the receptor will make CAR NK cells a more effective tumor killing machine. This may mean that they can target solid cancers, and so far, CAR-T therapy has proven difficult. “Gene-edited NK cells will become one of the key drugs for future off-the-shelf CAR therapies, especially for solid tumors,” said Rick Morgan, senior vice president of Editas Medicine, which is collaborating with Sandhill Therapeutics in Dallas, Texas Develop NK cell therapy.

Rezvani is also looking for ways to make CAR NK cells fight against solid tumors such as glioblastoma. At the same time, Sadelain has been exploring whether stem cells can become a permanent standardized source of NK or T cells for oncology. Sadelain said: “We are discussing the potential of cultivating one clone to produce cells for thousands of patients.” Fate Therapeutics is an immunotherapy company based in La Jolla, California that has a variety of stem cell-derived cell products in clinical trials. .

Leading methods for cancer cell therapy have not yet appeared, but the research on allogeneic CAR T and CAR NK cells is accelerating. “Three or four years ago, I would very much doubt the allogeneic approach, but we have already obtained data from Katy Rezvani and some allogeneic data,” Levin said. “It looks promising.” It remains to be seen whether autologous cells are completely abandoned in favor of a theoretically more cost-effective off-the-shelf method, or whether the method becomes part of a wider therapeutic area. In the end, this may not matter. “Patients and payers don’t care whether it is autologous or allogeneic,” Pule said. “As long as it works.”

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