Cell therapies like CAR-T are an extraordinary new class of drugs that have the potential to successfully treat cancer. Several obstacles hinder creation of optimal individual treatments for patients. Collecting cells from patients before chemotherapy while logistics are still straightforward appears to be a good approach.
What is cell therapy and how is it made?
Cell therapy is the use of immune cells, derived from a healthy donor or the patient, to treat disease. This approach was first employed in the 1950s to treat leukemia by transplanting bone marrow from a healthy donor to the patient, whose own cancerous marrow was ablatedremoved from the surface of an object, such as an organ; ablation can be done by scraping, cutting, or heating tissue with chemotherapy.1Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. New England Journal of Medicine. 1957 Sep 12;257(11):491-6. A new generation of cell therapy exists in which the transplanted cells are genetically engineered to recognize and kill many different cancers, not just leukemias. The most common type of this cell therapy is called “CAR-T,” which is an important treatment option because it has the potential to cure certain types of cancer.2Emily Whitehead, first pediatric patient to receive CAR T-Cell therapy, celebrates cure 10 years later. Children’s Hospital of Philadelphia. May 11, 2022. Viewed August 24, 2023. However, many patients run into barriers while trying to access this treatment.
CAR-T stands for chimeric antigen receptor T cell therapy. The so-called chimeric antigen receptor is the synthetic technology introduced into the T cell that helps it “see” cancer cells that it couldn’t before.3CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. National Cancer Institute. March 10, 2022. Viewed August 24, 2023. In addition to helping the T cells recognize the cancer cell, the receptor also switches the T cells on so that they can kill the cancer cell after seeing it. The CAR enables the T cell to both see and become activated in the presence of cancer cells.
Like other cell therapies, CAR-T cells can be autologous (made from the patient who is receiving it) or allogeneic (made from a healthy, unrelated donor). Typically, cells are collected using a procedure called leukapheresis, a very safe technique first developed in the 1950s.4Millward BL, Hoeltge GA. The historical development of automated hemapheresis. Journal of Clinical Apheresis. 1982;1(1):25-32. Leukapheresis begins when blood is taken from the donor by intravenous line into a machine which selectively removes the white blood cells (leukocytes), sending them to an attached bag (the leukopak). Although the process only takes a few hours, it can take weeks to schedule because apheresisa technology separating donated blood components to treat certain illnesses facilities are typically very busy.
Once a leukopak is created, it is sent to the cell therapy manufacturer where the desired immune cells are purified and the CAR is introduced into the T cells. The resulting CAR-T cells are then frozen in small quantities which correspond to individual doses. For autologous cell therapies, the CAR-T cells will only be given to the same patient they were made from. For allogeneic cell therapies, many doses are made from a single leukopak. They may be used for many different patients. The process of creating a CAR-T dose ready for infusion from a leukopak can take anywhere from a couple days to two weeks, depending on the manufacturing process.
Some newer approaches to making CAR-T do not involve any manipulation of cells outside of the patient’s body. In these cases, the CAR is introduced into the T cells within the patient’s body.5Pioneering the future of immunotherapy by reprogramming T cells in vivo. Umoja Biopharma. Viewed August 24, 2023; A new, big, bold idea to fight cancer. Siren Biotechnology. Viewed August 24, 2023; Engineered cells as medicines. Sana Biotechnology. Viewed August 24, 2023. This method of in vivo CAR-T manufacturing remains unproven but is promising nonetheless.
CAR-T is a challenging drug for patients to access
Given that several FDA-approved CAR-T options exist and that there are more than a thousand actively recruiting trials of cell therapies for many different types of cancer,6Wang V, Gauthier M, Decot V, Reppel L, Bensoussan D. Systematic review on CAR-T cell clinical trials up to 2022: academic center input. Cancers (Basel). 2023 Feb 4;15(4):1003. one might expect it to be easy for patients to access. However, studies show that patients find it very difficult to enter trials; in fact, fewer than 5% who want to actually do so.7Unger JM, Cook E, Tai E, Bleyer A. The role of clinical trial participation in cancer research: barriers, evidence, and strategies. American Society of Clinical Oncology Educational Book. 2016;35:185-98; Rimel BJ. Clinical trial accrual: obstacles and opportunities. Frontiers in Oncology. 2016 Apr 25;6:103.
While there are many promising CAR-T applications, only six CAR-Ts are FDA-approved to date. These approvals are only for certain types of blood cancer, and none of these are approved for first-linethe initial or first treatment recommended for a disease or illness use.8Chimeric Antigen Receptor (CAR) T-Cell Therapy. Leukemia & Lymphoma Society. Viewed August 24, 2023. Thus, most cancer patients interested in CAR-T are forced to endure both the standard of care (conventionalthe cancer care offered by conventionally trained physicians and most hospitals; examples are chemotherapy, surgery, and radiotherapy) treatments and the inherent challenges of finding and enrolling in a trial.
All of the FDA-approved CAR-T therapies available today are autologous. One advantage of autologous therapy is that the patient does not need a compatible donor since they are their own donor. There is no risk that a transfused therapy will be rejected (graft versus host disease). However, because people have already started chemotherapy before qualifying for CAR-T, the cells used to make their future cell therapy are already damaged by the chemotherapy before being collected.9Das RK, Vernau L, Grupp SA, Barrett DM. Naïve T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Discovery. 2019 Apr;9(4):492-499. In addition, it is challenging to schedule a leukopheresis because it must sync with the patient’s chemotherapy regimen and overall health.10Chen AJ, Zhang J, Agarwal A, Lakdawalla DN. Value of reducing wait times for chimeric antigen receptor T-Cell treatment: evidence from randomized controlled trial data on tisagenlecleucel for diffuse large B-cell lymphoma. Value in Health. 2022 Aug;25(8):1344-1351. The lack of insurance pre-authorization can also cause significant delays.11Personal communication, Dr. Rayne Rouce, Texas Children’s Hospital For people with advanced cancer, waiting an additional month or two to get CAR-T due to any combination of these reasons is life-threatening.
There has been hope among some scientists that allogeneic CAR-T therapies could solve these problems. Because they are made from a healthy donor, the cells are undamaged by previous rounds of treatment. Allogeneic therapies are made in advance so the complicated logistics of scheduling a leukopheresis don’t apply. However, despite being made from healthy cells with simpler manufacturing logistics, allogeneic cell therapies have not been as safe or effective as hoped. A major challenge with allogeneic CAR-Ts is that the cells they are made from must be manipulated to prevent rejection. There is growing evidence that such manipulations can affect the efficacy of allogeneic CAR-Ts, as they have consistently underperformed relative to their autologous counterparts to date.12Elsallab M, Ellithi M, Hempel S, Abdel-Azim H, Abou-El-Enein M. Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis. Cancer Gene Therapy. 2023 Jun;30(6):845-854; Allogene Therapeutics provides additional ALLO-501/501A phase 1 data in an oral presentation at the International Conference on Malignant Lymphoma (ICML) Lugano. Allogene Therapeutics. June 15, 2023. Viewed August 24, 2023; Plieth J. Ash 2021—Precision moves quickly to deal with allo disappointment. December 12, 2021. Viewed August 24, 2023.
Can autologous cell therapy access be improved?
Even before it was known that allogenic CAR-T therapies were not a panacea, scientists and clinicians were interested in improving autologous approaches.
It is remarkable that autologous cell therapies work at all. The immune cells from which they are made are damaged by multiple lines of chemotherapy and subjected to the ravages of advanced disease, and yet still go on to make a treatment that can cure an advanced cancer patient.13Emily Whitehead, first pediatric patient to receive CAR T-Cell therapy, celebrates cure 10 years later. Children’s Hospital of Philadelphia. May 11, 2022. Viewed August 24, 2023. Scientists have imagined that cure or remission would be more common if the CAR-T were made from patients’ cells before chemotherapy exposure. This would also solve the logistical issues of late stage leukopheresis, since that would have been done in advance, just as it is for allogeneic approaches.
In fact, there have been multiple initiatives to collect, freeze, and store leukopaks from early stage patients for future autologous CAR-T manufacturing. One such effort briefly existed at the University of Chicago14Riedell PA, Kline JP, Gideon JM, Wickrema A, Bishop MR. Navigating dilemmas in treatment choice: our approach to supplemental apheresis prior to enrollment in early-phase cellular therapy clinical trials. Transplantation and Cellular Therapy. 2021 Feb;27(2):105-107. and another is temporarily occurring at the National Institutes of Health.15Leukapheresis for CAR or Adoptive Cell Therapy Manufacturing. ClinicalTrials.gov. August 24, 2023. Viewed August 24, 2023. In these cases, the costs of collecting and storing the cells are covered by grants. The problem with relying on grants is that the monetary support is limited—when the grants end, the early cell collections halt. It is not a solution that can be scaled up to help patients everywhere, even though it is supported by the medical community.
CellVault was an early attempt to sustainably conduct early aphereses without grant money.16Cell Vault joins the fight against cancer, raising $1 million in early funding for first-ever T-Cell cryopreservation bank. Biospace. July 16, 2019. Viewed August 24, 2023. Their model was to charge healthy people to bank their cells, before a cancer diagnosis, but this was very problematic. The biggest issue was that they did not have buy-in from the cell therapy field: Nobody was willing to accept the cells they were collecting and storing to make a treatment for a patient. Their model was also very expensive for the participants, worsening health inequities instead of narrowing them. The predatory nature of the business was ultimately rejected by leading scientists and physicians in the field as well as patient advocacy groups.17Lanese N. Immune cell bank bets on future CAR T success. The Scientist. August 16, 2019. Viewed August 24, 2023; Levine BL, Munsie M, Levine AD, Ikonomou L; International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy. The peril of the promise of speculative cell banking: statement from the ISCT Committee on the Ethics of Cell and Gene Therapy. Cytotherapy. 2022 Oct;24(10):977-978. CellVault is no longer active.
Learning from CellVault’s mistakes, we at Achieve Clinics have developed a completely new approach that can support early apheresis sustainably, with critical clinical and industry buy-in. To begin with, our focus is on helping the most vulnerable population: patients, not healthy people who may never get cancer.
Furthermore, cells are collected and stored in a way that is acceptable for cell therapy manufacturing. Cell therapy developers approaching clinical trials are already partnering with Achieve Clinics, so when Achieve offers apheresis to patients, they can know that real options exist for them. And finally, Achieve Clinics does not charge patients anything. Achieve covers its costs by having the drug companies pay for access to the patients and their cells.
With Achieve Clinics, people with cancer will have a zero-cost option to improve access to future cell therapies. Patients can be empowered to bank their own leukopaks before their T cells are damaged by chemotherapy. These leukopaks can be sent immediately for manufacturing once a patient qualifies for a trial partnered with Achieve. Additional information can be found at www.achieveclinics.com.
The Achieve Clinics model is not perfect. For example, Achieve cannot guarantee that an early stage patient will be enrolled in a trial—that decision still remains up to the trial sponsor. Still, it is the best chance for patients to have zero-cost, streamlined access to a cutting-edge cell therapy made from healthier cells. Even if a patient does not get a cell therapy themselves, they can still help future patients by donating their cells for research use. Achieve Clinics is dedicated to providing as much benefit to as many current and future patients as possible.
Cell therapies like CAR-T are an extraordinary new class of drugs that have the potential to successfully treat cancer. Autologous CAR-T therapies are currently the most effective, with six FDA approvals and hundreds more in development. But this approach is complicated by its reliance on cells exposed to and damaged by chemotherapy, as well as the logistical burdens of obtaining those cells from advanced cancer patients. Allogeneic CAR-Ts are made from healthy cells well in advance of a patient’s need for them, seemingly addressing the shortcomings of autologous CAR-T. However, clinical data has shown that allogeneic CAR-Ts are less effective than their autologous counterparts.
There is a solution that aims to capture the advantages of allogeneic CAR-Ts and marry them with the improved efficacy of autologous. Collecting cells from patients before chemotherapy while leukopheresis logistics are still straightforward appears to be a workable compromise. This approach is gaining acceptance in the medical community, as Achieve Clinics is in discussions to launch at leading cancer hospitals in Seattle and Houston. In time, Achieve Clinics will bring their solution to cancer patients everywhere, ensuring that anyone can access cutting-edge autologous cell therapies.
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