Gene Therapies: What to Know

David Israel was diagnosed with lymphoma in 2015, the start of a two-year gauntlet of treatments including chemotherapy and a stem cell transplant. The cancer kept winning, and in the summer of 2017, Israel was told he had six months to live. Then his doctor suggested one more last-ditch option: a clinical trial of a gene therapy known as a chimeric antigen receptor T cell. The one-time CAR-T-cell treatment eradicated Israel’s cancer, and he hasn’t needed any other treatments since. “Being 58 at the time with two teenage sons, I decided the potential reward of participating in the study was greater than the risk,” says Israel, now 62, an executive recruiter in the Seattle area who received care from the Seattle Cancer Care Alliance, clinical partner of the Fred Hutchinson Cancer Research Center. “Without this cutting-edge treatment, I wouldn’t be here today.”

CAR-T-cell treatments are personalized therapies made from patients’ own immune cells, and two have been approved by the Food and Drug Administration to treat leukemia and lymphoma. But some patients don’t respond to the therapies, while others suffer a dangerous immune overreaction to them, and Israel was able to join a trial designed to improve CAR-T responses. In August 2017, Israel’s T cells were collected from his blood and their genes were altered to recognize and target CD19, a protein on the surface of lymphoma cells. The engineered T cells were infused back into his body in September. By the end of the year, he was cancer-free.

[See: 10 Innovations in Cancer Therapy. ]

The therapy Israel received, called lisocabtagene maraleucel, or liso-cel, is among a wave of new gene and cell therapies that are under development to treat cancer, blindness, and a range of inherited diseases caused by faulty genes. Some of these emerging treatments employ the new gene-editing technique CRISPR-Cas9 to snip out disease-causing genes, while others involve knitting in corrected copies of those genes into the body, where they pump out proteins needed to relieve symptoms. Gene-editing technology is being deployed against COVID-19, too: The FDA recently cleared a device that uses CRISPR to detect the virus’s DNA and report its presence in just an hour.

Current research on CAR-T treatments is aimed at improving both the safety and efficacy of the technology. “There’s an endless number of options for changing CAR-T cells to make them function better,” says David Maloney, who treated Israel and is medical director of cellular immunotherapy at Fred Hutchinson. Liso-cel, for example, is a fine-tuning of the mixture of two key types of immune cells: CD8s, which hunt down and destroy cancer cells, and CD4s, often called “helper” T cells because they boost the ability of CD8s to do their jobs. Liso-cel is made and administered back to patients as an equal mix of CD8 and CD4 T cells, while earlier CAR-T treatments contain a random selection of those cells. It’s still too early to know, but “the balanced mixture could provide an advantageous benefit-to-risk ratio for the patients,” Maloney says. The response rate among 256 patients in a clinical trial of the treatment was 73%, with most responses lasting for a year or more, according to data released in December 2019.

CRISPR’s Debut

CAR-T cells are now being engineered to target other cancer-associated proteins, including one that is prevalent in multiple myeloma. When one such CAR-T therapy, idecabtagene vicleucel, or ide-cel, was tested in 128 patients who had relapsed after receiving as many as three other treatments, 73% responded.

“That could be a game changer” for multiple myeloma patients, who often endure years of harsh chemotherapy and bone marrow transplants, says Nina Shah, associate professor at the UCSF Helen Diller Family Comprehensive Cancer Center and one of the investigators in the clinical trial. “Some patients are living now one or two years and haven’t needed any chemotherapy since.”

Ide-cel is on its way to the FDA for review, but its developers are already working on a way to improve it, building on research by others that has shown how to enrich the CAR-T cells so they mimic “memory” T cells, which can persist in the body for long periods. The enriched cells might have an anti-myeloma effect for longer, and perhaps be reinvigorated in a recurrence, Shah explains. It’s still early in the testing, but two of the first patients who received the enhanced version of ide-cel were still responding to their CAR-T treatment 18 months later.

There is one major drawback of all of these CAR-T therapies: Because they have to be tailored from immune cells that are taken from a patient, they can take three weeks or more to produce. So now several biotechnology companies are working on so-called off-the-shelf CAR-T treatments made from healthy donor cells that can be stored and administered on demand.

[READ: What Is Inflammatory Breast Cancer?]

“The appeal really is the speed,” says Alex Herrera, assistant professor in the department of hematology and hematopoietic cell transplantation at City of Hope in Duarte, California. “Some patients with aggressive cancer don’t want to sit around waiting to get their cells back,” Herrera says. Or by the time three weeks have passed, they may be too sick to receive the engineered cells. “If you have something that’s essentially like a drug, you can treat them right away.”

Off-the-shelf treatments are still in trials, but early results look promising. Twelve patients with non-Hodgkin lymphoma who relapsed after conventional treatments saw their cancer recede after receiving ALLO-501, a treatment made from donor cells, researchers reported in May. Its inventors engineered the therapy to prevent a dangerous rejection that can occur in people receiving donor cells by removing a specific gene on the T cell’s receptor. There were no cases of the reaction during the trial.

Now researchers are using CRISPR gene-editing techniques in the hopes of making off-the-shelf treatments even safer and applicable to a wider range of patients. In addition to deleting genes that cause the dangerous immune reactions, they’re using CRISPR to insert the CAR — the receptor that binds to the protein on cancer cells, allowing the immune cells to attack — directly into the T cell’s genome, rather than using an inactivated virus to carry it into the cell, as the current generation of CAR-T treatments do. “It’s elegant, in that the gene-editing technology allows you to knock out what you don’t want around and knock in whatever mediates the anti-cancer effect, all in one step,” Herrera says. Off-the-shelf CAR-Ts made with CRISPR are now being tested in patients with several types of blood cancers, as well as in those with some solid cancers, such as kidney tumors.

Replacing Faulty Genes

CRISPR is also being deployed in the fight against inherited illnesses, including sickle cell disease, which affects some 100,000 Americans, according to the Centers for Disease Control and Prevention. Sickle cell is caused by a mutation in the gene that makes hemoglobin, the protein that carries oxygen in red blood cells. Those cells become misshapen and clump up, leading to painful bouts of inflammation and ultimately organ damage. An experimental therapy called CTX001 involves removing blood-forming stem cells from patients and engineering them to disable a gene “switch” that normally instructs stem cells that it’s time to stop producing fetal hemoglobin and start producing adult hemoglobin.

The idea is to “trick stem cells into making more fetal hemoglobin,” which can help stabilize blood cells in patients, explains Haydar Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare’s Sarah Cannon Research Institute and The Children’s Hospital at TriStar Centennial in Nashville. The proportion of fetal hemoglobin in the bloodstream of a woman treated in the trial Frangoul is participating in skyrocketed from 9% to 47% in the six months following the infusion, according to research presented in May. She reported no pain crises during that time.

The therapy is also being tried in patients with beta thalassemia, which causes a shortage of red blood cells that can only be treated with frequent blood transfusions. The first two patients in that trial no longer needed transfusions within months of receiving the therapy.

A different gene therapy called LentiGlobin is also being investigated for patients with these blood disorders. For this treatment, an inactivated virus is used to insert a functional copy of the gene that makes normal hemoglobin into blood-forming stem cells, which are then infused back into patients. Early results are encouraging, Frangoul says. But the CRISPR therapy could have an advantage. “When you’re using a viral vector, you’re inserting some of the viral DNA into the genome along with the target gene,” he says. “You could have side effects related to unintentional insertions. So both technologies are encouraging, but we’ll need much longer follow-up to see how patients are doing.”

The rise of CRISPR has brought with it some controversy, given that it’s possible to use it to edit the DNA of human embryos. In 2018, a Chinese biophysicist announced he had done so to make the embryos immune to HIV, the virus that causes AIDS. He was ultimately sentenced to three years in prison for violating laws related to the practice of medicine in China, and scientists around the world sounded the alarm that other researchers could use CRISPR in ethically questionable ways.

Still, the promise that CRISPR could reverse hundreds of debilitating diseases has launched several human trials. In March, it was announced that a patient at Oregon Health & Science University had become the first to have the CRISPR technology applied directly to the eye. The therapy was developed to treat Leber congenital amaurosis 10, a disease that typically causes blindness in childhood. It works by deleting a mutation in a gene called CEP290. The mutation depletes the protein that the gene would normally make, leading to a degeneration of photoreceptor cells in the eye and vision loss.

[Read: 9 Ways to Spot Skin Cancer Before It Kills.]

No More Stop Sign

“We’re going in and using CRISPR to take out the mutation that has created a stop sign for the production of the protein,” says Mark Pennesi, chief of the Paul H. Casey Ophthalmic Genetics Division at the OHSU Casey Eye Institute. The hope is that after the mutation is removed, the CEP290 gene will start producing the protein that photoreceptors need to function properly.

One gene therapy already on the market to treat a different inherited eye disorder, Luxturna, uses a virus to insert a functional copy of the faulty gene into the eye. That’s not possible with CEP290 because the gene is too large to fit into the inactivated virus, Pennesi says. “CRISPR really holds a lot of potential,” he says, because there are many different inherited retinal diseases that may not be treatable with traditional gene therapy.

The COVID-19 pandemic forced many developers of new gene therapy and CRISPR treatments to temporarily halt their trials to prevent participants from potential exposure to the virus at medical facilities. Meanwhile, these technologies could prove useful in detecting and treating coronaviruses. Besides the new FDA-approved CRISPR-based diagnostic test, researchers at Baylor University in Texas are working on off-the-shelf T-cell therapies to fight the virus, and a team led by Massachusetts General Hospital and the University of Pennsylvania Perelman School of Medicine is developing a COVID-19 vaccine using gene-therapy technology. Drug giant Novartis joined the effort to speed it into development.

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