Cancer Treatment Could Get Faster with Genetic Engineering

Since 2017, a personalized immunotherapy called Chimeric Antigen Receptor, or CAR-T cell treatment, has worked wonders to treat patients with blood cancers such as leukemia. 

But when it comes to treating solid tumor cancers, such as lung, breast and kidney cancers that make up the bulk of these malignancies, this type of immune cell therapy has fallen short.

“There is a major push now to understand how to make CAR-T cells efficacious in solid tumors,” said Stephen Hatfield, assistant professor in pharmaceutical sciences at Northeastern’s Bouvé College of Health Sciences. “Right now, clinically, this approach has not been successful.”

A major obstacle is the low oxygen environment of solid tumors, which generates molecules that essentially turn off the cancer-fighting ability of specially engineered CAR T-cells, Hatfield said. 

But he has collaborated with colleagues to overcome this critical barrier by using a type of genetic engineering known as base editing – a precise gene-editing technique that makes targeted changes to molecular DNA.

In a paper published in Nature Communications, they showed that in humanized mouse models they were able to eliminate the ability of molecules known as “negative regulators” to suppress the immune function of CAR-T cells in the low oxygen environment of solid tumors. 

The results proved successful for a malignancy known as non-small cell lung cancer. The gene edits can also be used with other solid tumor cancers, said Ryan Murray, who received his Ph.D in cell and molecular biology from Northeastern in 2024 and is a co-author of the study. “The potential is massive,” he said. 

Equally exciting, Hatfield said, was the ability of researchers to take the highly personalized treatment of CAR-T cell-based immunotherapy and make it available “off-the-shelf,” so cancer patients don’t have to wait for their own cells to be harvested and genetically engineered.

In CAR-T treatment, immune cells known as T cells are genetically engineered in the lab to produce a protein called a chimeric antigen receptor, which allows the immune cells to recognize and kill cancer cells.

But the type of molecules produced in the oxygen-depleted environment created by fast-growing solid tumors prevent immune cells from doing their job, Hatfield said.

“We want to fortify CAR-T cells,” Hatfield said about the research. “We want to make them resistant to these immune suppressive mechanisms.” 

Together with colleagues at the Cambridge-based biotech Beam Therapeutics, the scientists used base editing to make up to six edits in cells and selectively edit out critical immune suppressive molecules that go by an alphabet soup of names: A2A, PD-1 and TGF beta.

Base editing allows researchers to change a single building block of DNA, called a nucleotide, at a time, Hatfield said, “reducing the amount of genetic manipulation” and limiting adverse effects.

Using a process known as multiplexing, base editing allowed researchers  to “knock out” six individual genes with no side effects, Hatfield said, noting that the edited T cells were “perfectly viable.” 

 “It is the first time to our knowledge this level of editing has been achieved,” Murray said. “This strategy shows the need to attack multiple spokes of the tumors’ defenses to be effective.”

The approach was effective in killing cancer cells in mice implanted with human immune cells, leading to “complete tumor elimination,” Hatfield said. He said the discovery is leading to hopes that enough money can be raised to consider such an approach in clinical trials in humans.

Base editing also allowed for the use of these CAR-T cells “off-the-shelf”, which if translated into actual cancer patient care could save immense amounts of time and money, Hatfield said.

CAR-T treatment currently is highly personalized, he said, explaining that a patient’s T cells are removed, engineered and then put back into the same patient.  

The process can take months and is patient specific, he said. The patient in the next bed cannot use the same product because their immune system would attack the cells as foreign through what is known as  graft versus host disease or other autoimmune reactions.

But using base editing, researchers were able to engineer CAR-T cells in a way that prevented them from being eliminated by the host immune system or attacking the host patient,  Hatfield said.

“You could use it for any patient that has a tumor that expresses a particular antigen,” he said. That means the cells could be produced in larger, scalable amounts in shorter periods of time and frozen in anticipation of patient use.

Murray, an entrepreneur who co-founded KiraGen Bio, a Boston-based biotechnology company, called immunotherapy for solid tumors “the final frontier.”

He said the next step toward trying these new experimental therapies in humans was to get preclinical studies approved by the federal Food and Drug Administration. 

“The path has been paved by universities and companies working on these” technologies, he said.