A Question of Time
Another aspect of CAR T-cell therapy that is proving difficult is its delivery.
Forster outlined that the process involves first leukapheresis, in which T cells are obtained from a blood draw. These are then genetically modified to express chimeric antigen receptors before being multiplied in the laboratory and introduced to the patient.
This process can take several weeks, during which patients may require bridging treatment, such as chemotherapy or radiotherapy, to keep their cancer under control. “Sometimes, patients with solid tumors who are in later lines of therapy may not have the luxury of time to be able to wait for all of these steps,” Aggarwal said.
There is also the question of whether a bespoke treatment can be scaled up so that it can be delivered to more patients in a more timely manner.
“There are certainly lessons to be learned from use of off-the-shelf CAR T-cell products” in hematologic malignancies, she noted, “but we’re just not there yet in lung cancer.”
Life-Threatening Toxicities
To improve the chances of engraftment when the CAR T cells are introduced, patients will require prior lymphodepletion with chemotherapy.
This, Forster said, is a “relatively intensive part of treatment.” However, “if you just give immune cells to somebody, when the host body is already full of immune cells,” the CAR T cells are unlikely to engraft, and “so you need to create space for those cells to develop.”
“What you want is not an immediate effect” but rather an immune “memory” that will give an ongoing benefit, he underscored.
Many patients will need to stay in the hospital one or more nights “because when you bring T cells to a tumor, you get cytokine release syndrome [CRS],” Herbst said. This can cause hypotension, fever, and chills, similar to a viral response.
“So patients can get sick,” which in turn requires treatment and follow-up. That puts a “big burden on the health system” and is a major issue, Herbst said.
Patients are also at a risk for “significant neurotoxicity,” said session cochair Amy Moore, PhD, vice president of Global Engagement and Patient Partnerships, LUNGevity Foundation, Chicago. This, alongside CRS, “can be life threatening for our patients.”
Lengthy hospital stays also have a psychosocial impact on the patient and their quality of life, she emphasized, especially when they are treated in a center far away from family and loved ones.
“We’ve also heard anecdotally some reports recently of secondary malignancies” with CAR T cell and other therapies, and that’s something that needs to be monitored as more patients go on these treatments, she said.
‘At What Cost’ to Patients?
The difficulties faced by patients in receiving CAR T-cell therapy go far beyond the practicalities of generating the cells or the risks associated with lymphodepletion, however.
“These therapies are extraordinarily expensive,” although that has to be weighed against the cost of years of ongoing treatment with immunotherapy, Moore said.
Moreover, as CAR T-cell therapies are a “last resort” option, patients have to “exhaust all other treatments” before being eligible, she continued. There’s significant prior authorization challenges, which means patients “have to go through many hurdles before they can qualify for treatment with these therapies.”
This typically involves having numerous laboratory tests, which can add up to out-of-pocket expenses for patients often reaching tens of thousands of dollars, Moore said.
Another issue is that they must be administered in certified treatment centers, and there are a limited number of those in the United States, she added.
This increases the risk of heightening disparities, as patients are “forced to travel, seek lodging, and have meal expenses,” and the costs “are not trivial,” Moore underlined. “It can rack up quickly and mount to $10,000 or more.”
For physicians, there are difficulties in terms of the logistics of following up with those patients who need to be treated at centers on the other side of the country, uncertainties around reimbursement, and restrictions in terms of staff time and resources, among others.
“I’m as excited as you are at the science,” but it is the implementation that is at issue, Moore said. In other words, there is the offer of a cure with CAR T-cell therapy, but “at what cost?”
“For patients, these considerations are real and they’re significant” and “we have to ensure that what we’re doing is in service of people with cancer,” she emphasized.
No funding was declared. Aggarwal declared relationships with Genentech, Celgene, AstraZeneca, Daiichi Sankyo, Turning Point, Janssen, Pfizer, Lilly, Merck, Regeneron/Sanofi, Eisai, BeiGene, Boehringer Ingelheim, Blueprint Genetics, and Shionogi. Forster declared relationships with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Achilles, Amgen, Bayer, Bristol-Myers Squibb, Celgene, EQRx, GSK, Immutep, Janssen, Merck, Oxford Vacmedix, PharmaMar, Roche, Takeda, Syncorp, Transgene, and Ultrahuman. Moore declared no relevant financial relationships.