Cancer cell amidst flowing red blood cells.
In April 2012, a seven-year-old with acute lymphoblastic leukemia named Emily Whitehead became the first pediatric patient ever to receive an experimental new blood cancer treatment.
For many years, the mainstream approach for treating blood cancers has been to use very high doses of chemotherapy to wipe out the patient’s entire blood cell production systems along with the cancerous cells. Then, a bone marrow transplant from a matched donor is required to restore the patient’s ability to produce blood cells. All in all, the process is grueling and carries many side effects.
In Whitehead’s case, her disease had become resistant to chemotherapy, so she was not eligible for a bone marrow transplant. Given just weeks to live, physicians decided to trial CAR T-cell therapy, a then novel process which involved collecting her T cells, genetically reprogramming them to recognize her cancer, and infusing these modified T cells back into her blood. It worked - Whitehead went into remission and a new era of blood cancer medicines had been born.
Now twelve years later, there are six CAR T-cell therapies approved by the U.S. Food and Drug Administration, but there is a key limitation - each therapy has to be tailored and tested specifically for an individual patient’s disease, a laborious, costly and time-consuming process. Last year, one study highlighted that patients wait for an average of six months to begin treatment, with a quarter of them dying in the meantime. “Anything we can do to make cell engineering better for cancer patients cannot come soon enough,” says Fyodor Urnov, professor of molecular and cell biology at the University of California, Berkeley.
But around the world, from Switzerland to the U.S., scientists are pursuing a paradigm-shifting approach using a next-generation form of gene editing called base editing, with the aim of minimizing treatment side effects and ultimately being able to target any form of blood cancer.
At the end of May, researchers at the University of Basel published a study in Nature applying their approach in animal models and human cells. Using a protein target called CD45 which sits on the surface of all blood cells, a targeted form of chemotherapy delivered via an antibody-drug conjugate (ADC) is used to destroy all the diseased cells. At the same time, a stem cell transplant is administered, but these donor stem cells have been genetically tweaked in such a way that makes them invisible to the ADCs, an approach which they call shielding.
“The idea is to make a new blood system that is resistant to the treatment that we apply,” says Professor Lukas Jeker of the University of Basel, who led the study. “It’s made possible by these newer versions of genome editing, very precise tools which allow very small, targeted changes. We can edit the stem cells in a way that means the ADC can no longer bind, but the function of the cells is still preserved.”
Last summer, researchers from the University of Pennsylvania School of Medicine published a similar study in which they used base editing to engineer T cells to seek out the CD45 target on blood cancer cells. Once again, a stem cell transplant happens simultaneously, but the stem cells have also been base edited to keep them shielded from the roaming T cells.
“The shielding is a technically very stylish idea,” says Urnov. “One of the most powerful implications is that you can actually harvest the patient's own bone marrow cells, gene edit them to keep them safe from the therapy, and put them back in.”
Improving Patient Access
Rachel Haurwitz, president and CEO of Caribou Biosciences, a company developing their own off-the-shelf CAR T-cell therapies to treat blood cancer, described the idea of a universal blood cancer therapy as intriguing, and an example of the advances which have been made in genome editing.
“First generation CRISPR-Cas9 technologies were very good at genome editing for academic or laboratory purposes, but often led to genome edits at unintended targets,” she says. “Advancements in the CRISPR field have dramatically reduced these errors. [However] I feel that a combined CRISPR-edited CAR T-cell and hematopoietic stem cell (HSC) approach would require significantly more assessment in animal or non-clinical models, especially examining the long-term effects of transplanting edited HSCs, in hopes of reducing risks to patient safety.”
Jeker has founded a spin-off company called Cimeio Therapeutics with the goal of pushing the approach towards the clinic, while continuing to conduct more preclinical studies in his research lab.
As well as cancer, he believes that the same approach could be used in a number of autoimmune diseases such as lupus, which are caused by lymphocytes reacting against the body. “We could use this approach to actively deplete autoreactive B cells and T cells with a drug therapy, while replacing them with a new immune system which has been edited to shield it from the drug,” he says. “So it will be a very deep reset of the immune system. Multiple sclerosis is another autoimmune disease with good mouse models where we could test the approach.”
For blood cancer patients, Haurwitz says that the goal of a universal treatment should be an off-the-shelf therapy which can be made readily available to all patients at any time, something which Jeker believes should be possible with his approach as ADCs are by definition, off-the-shelf treatments, while genetically engineering stem cells only takes a matter of days. Haurwitz points out that the issue with many current CAR T-cell therapies is not only the long manufacturing process, but the fact that delivering a bespoke patient-specific cell therapy product is only possible at large, top-tier healthcare institutions.
“If a universal CAR T-cell is made for all blood cancers, then that product would need to be readily available to patients regardless of their place in the manufacturing queue, if they are close to a center of excellence, or if they have a cancer that is progressing rapidly,” she says. “Developing a CAR T-cell therapy that can treat any blood cancer would be incredible but only impactful if patients can receive that therapy.”
In the meantime, Emily Whitehead just finished her college freshman year at the University of Pennsylvania, near the medical center where she was treated with CAR T-cell therapy as a child. Her remarkable story is proof that scientific breakthroughs can save lives and leave medicine forever changed.
Thank you to David Cox for additional research and reporting on this article.
