A Decade On, the First CAR-T Cancer Immunotherapy Patients Are Declared "Cured"
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A follow-up study examining two of the first leukemia patients to be given CAR-T immunotherapy 10 years ago has shown they remain free of cancer cells, leading researchers to declare that they have been cured by the therapy.
Tackling B-cell cancer
The two patients in the study were dosed in 2010 by researchers at the University of Pennsylvania led by Carl June, a professor of immunotherapy at the university’s Perelman School of Medicine. Both patients were diagnosed with chronic lymphocytic leukemia (CLL), a chronic blood cancer that affects B cells, white blood cells that play an important role in antibody production.
One of the patients involved in the study, retired biochemist Doug Olson, was first diagnosed in 1996. Olson underwent chemotherapy in the early 2000s, which helped him into remission for five years. But by 2010, Olson’s cancer had re-emerged. “About 50% of my bone marrow was CLL,” explains Olson. Faced with playing what he describes as his “last card” – a full bone marrow transplant – Olson instead took up the option of CAR-T therapy.
What is CAR-T immunotherapy?
In CAR-T immunotherapy, chimeric antigen receptors (CARs) are artificially added to the surface of T cells, which help them to attach to the surface of cancer cells. In Olson’s case, these CAR T cells were originally sourced from his blood. Extracted cells are modified and then infused back into the patients. The modification process traditionally uses a viral vector to deliver the CAR protein coding sequence, although mRNA technology has more recently been used to modify cells.
Like most cancer treatments, only a subset of patients responds to CAR-T therapy – in CLL, roughly 25-35% show remission, although this statistic can dramatically increase when combined with other therapies. In Olson’s body, the treatment was a wild success. Initially the therapy produced strong side effects, says Dr. David Porter, an expert in CLL and the oncologist who first diagnosed Olson’s cancer. Olson felt like he had an intense bout of flu, but he was in fact experiencing tumor lysis syndrome, a side effect of masses of CLL cells being killed by the newly modified T cells. While this meant Olson required a stay in hospital, Porter points out that it is also a “testament to the potency of the therapy.”
Olson soon recovered, and a few weeks later, Porter called Olson with a new development. “He said, ‘Doug, we cannot find a single cancer cell in your body,’” Olson explains. This result was a preview of the incredible success that CAR-T therapy would produce in many patients with blood cancers, but the clinical poking and prodding of Olson’s body had only just begun.
A decade of follow-up
While follow-up for cancer patients traditionally involves a simple check-up to see whether they remain in remission or not, the US Food and Drug Administration (FDA) require patients given gene therapies, like CAR-T, to be monitored for the following 15 years. June asked his colleague, Dr. Joseph Melenhorst, to go a step further, and set up a lab with the express purpose of following their first patients over the subsequent decade.
The resulting study, published in Nature, reveals a detailed and sometimes surprising story of how the CAR-T cells have evolved over time in the patients’ bloodstreams.
The key findings, said June, were that no cancer cells remained in Olson’s body and that his modified T cells were detectable 10 years on. Some CAR-T cells lose their cancer-fighting ability and become what June calls “bystanders”, due to a little-understood process called T-cell exhaustion. But the cells that Melenhorst extracted from Olson remained ready to go another round, showing an ability to kill cancer cells in test tube experiments. What surprised the team even more was the makeup of these resilient slugger cells.
A surprise subset
There are several subsets of T cell, including natural killer cells, which are demarcated by their expression of a molecule called CD8. CD8+ T cells are thought to play the central role in battling cancer cells during immunotherapy.
But over the 10 years that Olson’s transplanted and modified cells remained in his body, the CD8+ cells population virtually disappeared, replaced by a supermajority of CD4+ T cells, also known as helper T cells. In wider immune responses, these cells play an important role, encouraging B cells and CD8+ cells to ramp up antibody production and kill infected cells respectively. But the team’s findings have given pause to consider whether CD4+ cells also play a more direct role in the suppression of cancerous cells, given the total absence of CD8+ cells in their patients’ bloodstreams.
New approvals and next steps
The team’s hope is that some of the findings from these patients can inform ongoing efforts to adapt CAR-T therapy for use in other types of cancer. Five different types of the therapy are currently approved. But none have yet been sanctioned by the FDA for CLL, mainly because of the number of other treatment options available to patients. Porter believes that approval will come in the near future, and progress is also being made elsewhere. June points to the FDA’s decision last year to grant Bristol Myers Squibb approval for the use of CAR T-cell therapy in multiple myeloma. This development is significant for two reasons – myeloma is the most common bone marrow cancer in adults, and the therapy doesn’t target the CD19 receptor that existing therapies home in on, rather exerting its effects via another molecule called the B-cell maturation antigen (BCMA). Eventually, June predicts, “basically all” blood cancers will come to be treated by CAR-T cell therapies.
Nevertheless, the therapy has proved less effective at targeting solid cancer, which makes up roughly 90% of cancers overall. This remains, to June, a big scientific challenge. Researchers studying these cancers have been unable to reproduce the kind of success seen with Olson’s CLL. This is due, June explains, both to the increased complexity of solid tumor structure and mechanisms that these cancers have evolved to evade the immune system. “There’s a need for a lot more research,” he says.
Additionally, it’s not yet clear whether the circulating T cells are still playing an active role in Olson’s body – June explains that Olson’s CLL might have been finally eradicated back in 2010, or may be repeatedly coming back, only to be brought to below a detectable limit by the remaining CD4+ cells. The aim to conduct further analysis to work out exactly what function this unexpected population still serves. What is clear, 25 years after Olson’s first diagnosis, is this: “Clinically, he’s cured,” June concludes.
Reference: Melenhorst JJ, Chen GM, Wang M, et al. Decade-long leukemia remissions with persistence of CD4+ CAR T cells. Nature. 2022. doi: 10.1038/s41586-021-04390-6
