Manufacturing innovations in CAR T cell therapies could be a game-changer for many late-stage cancer patients.
Cancer is the second-highest cause of death globally with about 70 per cent of deaths occurring in low- and middle-income countries. Drugs used for the treatment of cancers represent one-third of the top 15 bestsellers, with a forecasted 10.9 per cent compound annual growth rate (CAGR) leading up to 2030.1 Yet, the age of one-size-fits-all drug blockbusters is fading and with the average efficacy of current treatments to be as low as about 17.4 per cent,2 the future is looking to personalised approaches for cancer treatment.
CAR T Cell and How It Works
A paradigm shift in the innovation of the treatment of cancer is CAR T cell-based immunotherapy, whereby a patient’s own T cells are genetically engineered to fight cancer cells. Chimeric Antigen Receptors (CARs) are powerful engineered immune receptors that link recognition of defined specificity to immune effector functions. When these synthetic receptors are introduced into immune cells, typically T cells, these CAR T cells confer augmented T cell function. Once infused into the body, CAR T cells engraft and undergo extensive proliferation in the patient. Each CAR T cell can kill many cancer cells, and the treatment may promote immune surveillance to prevent tumour recurrence through antigen release, assisting tumour-infiltrating lymphocytes in attacking tumours, or their own persistence.
Unlike traditional cancer treatment such as radiation and chemotherapy, treating cancer by targeting tumour-specific traits such as surface proteins like CD19 or BCMA allows CAR T destruction of tumour cells with minimal collateral damage to healthy cells. Currently approved CAR T products are the donor’s engineered—and hence personalised—immune cells that are extracted, shipped to special manufacturing facilities, genetically modified, and returned for infusion into the patient. When cells are taken from a patient, manipulated, and returned to the same patient, the therapy is known to be autologous.
The most significant breakthroughs for CAR T immunotherapy has been for the treatment of haematological cancers. Although treatment advances have driven five-year survival rates to more than 90 per cent, the prognosis of refractory or relapsed malignant haematological cancer is poor. Those who survive relapse typically require hematopoietic stem cell transplantation to remain in remission. However, not all patients who relapse are eligible for hematopoietic stem cell transplantation. CAR T therapy as an alternative has demonstrated that ex vivo gene-modified autologous treatment can deliver cures to otherwise terminal cancer patients, offering an overall response rate of 86 per cent.3 However, at present, this success occurs for only a tiny portion of the cancer patient population as haematological cancers represent less than 10 per cent of all cancer malignancies. While intensive research is underway to expand the range of CAR T treatment to other cancer types, including solid malignancies, patient access remains restricted where CAR T is only available to late-stage “end-of-line” patients after exhausting other care options, termed as compassionate care or salvage therapy. Furthermore, CAR T treatments are the most expensive oncologic therapy to date due to the high list price, manufacturing costs, as well as monitoring and management of side effects and associated hospitalisation health costs.
Safety and Costs of CAR T Cancer Immunotherapy – Hurdles to Wider Patient Access
For these genetically modified, autologous haematological cancer cures, the pricing of CAR T cell immunotherapy is shockingly high and beyond the reach of the average person without financial assistance.
The current U.S. list prices for three U.S. Food and Drug Administration-approved CAR T immunotherapies, Kymriah, Yescarta and Breyanzi, are US$475K, $373K, and $410K, respectively. In addition to looking at the CAR T product price tag, the health effect brought about by CAR T immunotherapy as a medical intervention should be considered to understand its value for money.
A recent systematic literature review shows that most economic evaluations of CAR T to treat diffuse large B-cell lymphoma (a type of haematological cancer) assume a 6.5 to 8.5-year quality-adjusted life-year (QALY) gain, and costs per additional year of QALY are mostly calculated to be above US$50K.4,5 This is above the typical UK threshold of GBP 20K to 30K, and certainly above the affordability and reach of patients in many countries in the South, East, and Southeast Asia regions, which account for a significant share of global cancer cases.
In 2020, 9.5 million new cancer cases and 5.8 million cancer deaths were estimated in these Asian regions, corresponding to around half of the cancer burden worldwide. At this list price and economic value, most of the Asian population, including Singaporeans, are priced out of this curative treatment.
In addition to the high list price of the CAR T product itself, treatment of toxicity that arises as a side effect of CAR T immunotherapy is a significant cost determinant. In nearly all patients, CAR T cells induce marked elevations of systemic cytokine levels, termed cytokine release syndrome (CRS), with up to a third of patients in clinical trials developing severe CRS (CRS grades 3 and 4), which may be fatal if not expertly managed. In paediatric and adult acute pre–B-cell lymphoblastic leukaemia, the severity of the CRS can be associated with tumour burden, disease distribution, baseline inflammatory state, type of CAR T cell product and/or proliferative activity of the disease. Immune effector cells–associated neurologic syndrome (ICANS) is another adverse effect associated with CD19 and BCMA CAR T cells in up to half of the patients in clinical trials, which can lead to confusion, delirium and seizures, and can be potentially fatal or life-threatening. It is noteworthy that the risk for adverse events entrenches CAR T therapy as a third-line treatment, exacerbating the already restricted patient accessibility.
These significant toxic side effects require stays in the intensive care unit (ICU). With increasing clinical experience, CRS and ICANS are reversible. However, the associated side effects, treatment, longer hospitalisation stays and supportive care can potentially drive the total cost of the treatment to over US$ 1 million, more than double the cost of the already costly drug. A conservative estimate by simply adding the cost of medicine to the cost of CRS treatment produced a per-patient treatment cost range from US$487K for those without CRS to US$531K for those with severe CRS. Expert clinical management of CRS and ICANS are also currently available in a few healthcare centres in the world.
The safety concerns and the high pricing of autologous CAR T immunotherapy are barely on the cusp of acceptability for patients in rich countries. It is simply out of reach for most of Asia and the world’s population.
Is manufacturing innovation the answer to making cancer CAR T immunotherapy treatment safer and more affordable?
Manufacturing Innovations in CAR T Cell
At the Singapore-MIT Alliance for Research and Technology Critical Analytics for Manufacturing Personalized-Medicine (SMART-CAMP) Interdisciplinary Research Group, risk-adapted strategies for personalising CAR T cells based on predicted adverse effects is one approach we are taking to make safer CAR T products through innovations in novel bioanalytics.
For example, assessment of enzymatic secretions by immune cells from the patient can provide a window to how a patient will respond to CAR T treatment, including its side effects. Using a fully integrated system for multiplexed profiling of native immune single-cell enzyme secretion from 50 microlitres of blood, sample handling is eliminated, and the procedure is hands-free following the drawing of blood.
With a total analysis time of 60 minutes, the integrated platform performs six tasks of leukocyte extraction, cell washing, fluorescent enzyme substrate mixing, single-cell droplet making, droplet incubation, and real-time readout for leukocyte secretion profiling of neutrophil elastase, granzyme B, and metalloproteinase.6 This method can be adapted for enzymatic secretions of other immune cells such as CAR T cells, as well as expansion into the analysis of other types of enzymes. Enzymatic secretions of immune cells are direct indicators of clinical immune response and activity, and our results demonstrated donor-to-donor heterogeneity in their secretion profiles.
Understanding donor heterogeneity could lead to personalised immune profiling to identify patients at greater risk for severe CRS or ICANS and design CAR constructs with minimal CRS and/or ICANS toxic effects. Already, novel CAR constructs are being designed, and the SMART-CAMP enzymatic secretion platform could be employed to optimise and fine-tune the CAR constructs that minimise the risk of eliciting CRS and ICANs, without comprising T cell signalling and cytolytic properties. There is some evidence that a larger number of injected CAR T cells may cause severe CRS.7 With better CAR T cell phenotype profiling and selection, the number of cells injected could be reduced and possibly reduce severe adverse effects. Conversely, the platform can be utilised to identify secretions that correlate with CAR constructs and/or specific CAR T cell populations that are efficacious.
External biological, chemical or biophysical triggers are known to activate T cells differently and alter their secretion profiles. Using the SMART-CAMP enzymatic secretion platform to obtain optimal CAR T cell secretions, steps to refine the cells by selective CAR T cell activation/deactivation during manufacturing through the judicious use of biological, biophysical, or chemical triggers is also an exciting possibility.
The production of CAR T products involves many complicated steps, where each step has a potential risk for contamination by adventitious microorganisms. As mandated by regulatory bodies, CAR T products must go through a costly and lengthy product release safety testing to ensure the final injected product is free of pathogens. Production automation in a closed system and adherence to Good Manufacturing Practice (GMP) guidelines help reduce contamination opportunities and should make these events increasingly rare in the future but testing remains a necessity.
Today, many tests for adventitious agents such as bacteria and viruses rely on amplification through long culture periods to determine the existence of microorganisms. Further, current release safety testing is typically done at specialised laboratories that may not be available in the same region as a site of manufacture or patient treatment. For autologous CAR T treatment given to “end-of-line” cancer patients, these delays for product release can affect the likelihood of treatment success due to the progression of the disease, further complicating treatment beyond safety and cost. Thus, the design of innovative rapid assays for detecting adventitious microorganisms is highly desirable to reduce the lag time from manufacturing to patient infusion.
Recently, a multidisciplinary team involving researchers from SMART-CAMP, National University of Singapore (NUS), National University Hospital (NUH) and Massachusetts Institute of Technology (MIT) developed an assay that combined CRISPR and digital PCR technology to provide a quicker quantitative result, with less variability, for COVID-19 and Epstein-Barr viral loads in samples.8
The RApid DIgital Crispr Approach, or RADICA, utilises CRISPR-based isothermal amplification and digital PCR-based partitioning methods that can be completed in under an hour. RADICA, by offering sensitive quantitation and shortening assay times, therefore solves two bottlenecks in detecting adventitious microorganisms in CAR T cell manufacturing and release. Once the RADICA protocol is set up, adapting it to new viruses relevant to cell therapy manufacturing is straightforward, meaning more laboratories can potentially employ this assay in their manufacturing lines.
In addition, because the quantification of DNA/RNA by RADICA is absolute, quantitative confidence is higher and allows for inter-site comparisons. RADICA’s robustness of quantitation and ease of use are important considerations where skilled and highly trained labour in CAR T cell manufacturing is in short supply, for instance, in most ASEAN and Asian countries.
Blazing fast progress is made in advancing the development of CAR T for improved clinical efficacy as well as treatment of other cancer types, including solid tumours. While we look forward to the future, current CAR T technology is by no means a perfect solution. Despite success demonstrated as curatives of haematological cancers, bespoke treatment is costly and toxicity can be severe – hampering its widespread adoption.
We envision that manufacturing innovations that reduce safety burdens, from adverse events to sterility issues, can propel CAR T immunotherapy from third-line treatment to first- and second-lines of cancer treatment and enhance patient access to these immensely promising therapies. [APBN]
- KPMG. (2018). The future of oncology: A focused approach to winning in 2030. https://assets.kpmg/content/dam/kpmg/cn/pdf/en/2018/04/the-future-of-oncology.pdf
- Jardim, D. L., de Melo Gagliato, D., Nikanjam, M., Barkauskas, D. A., & Kurzrock, R. (2020). Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds. OncoImmunology, 9(1), 1710052. https://doi.org/10.1080/2162402x.2019.1710052
- Novartis. (2020). Novartis announces Kymriah® meets primary endpoint at interim analysis of pivotal study in follicular lymphoma. https://www.novartis.com/news/media-releases/novartis-announces-kymriah-meets-primary-endpoint-interim-analysis-pivotal-study-follicular-lymphoma
- Roth, J. A., Sullivan, S. D., Lin, V. W., Bansal, A., Purdum, A. G., Navale, L., Cheng, P., & Ramsey, S. D. (2018). Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States. Journal of Medical Economics, 21(12), 1238–1245. https://doi.org/10.1080/13696998.2018.1529674
- Healthcare Improvement Scotland. (2018). axicabtagene ciloleucel 0.4 – 2 x 108 cells dispersion for infusion dispersion for infusion (Yescarta®). Scottish Medicines Consortium. https://www.scottishmedicines.org.uk/media/4121/axicabtagene-ciloleucel-yescarta-final-nov2018-for-website.pdf
- Zeming, K. K., Lu, R., Woo, K. L., Sun, G., Quek, K. Y., Cheow, L. F., Chen, C. H., Han, J., & Lim, S. L. (2021). Multiplexed Single-Cell Leukocyte Enzymatic Secretion Profiling from Whole Blood Reveals Patient-Specific Immune Signature. Analytical Chemistry, 93(10), 4374–4382. https://doi.org/10.1021/acs.analchem.0c03512
- Hay, K. A., Hanafi, L. A., Li, D., Gust, J., Liles, W. C., Wurfel, M. M., López, J. A., Chen, J., Chung, D., Harju-Baker, S., Cherian, S., Chen, X., Riddell, S. R., Maloney, D. G., & Turtle, C. J. (2017). Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy. Blood, 130(21), 2295–2306. https://doi.org/10.1182/blood-2017-06-793141
- Wu, X., Chan, C., Lee, Y. H., Springs, S. L., Lu, T. K., & Yu, H. (2020). A Digital CRISPR-based Method for the Rapid Detection and Absolute Quantification of Viral Nucleic Acids. Biomaterials. Published. https://doi.org/10.1101/2020.11.03.20223602
About the Authors
Yie Hou Lee is the scientific director of Critical Analytics for Manufacturing Personalized-Medicine (CAMP) interdisciplinary research group at Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore. He provides leadership accountability for the delivery of portfolio and manages team performance to drive impactful deliverables of cell therapy manufacturing innovation. He is also an assistant professor at OBGYN-Academic Clinical Group in Duke-NUS Medical School, Singapore.
Michael Birnbaum is an associate professor in the Dept. of Biological Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research, and a Principal Investigator of Critical Analytics for Manufacturing Personalized-Medicine (CAMP) interdisciplinary research group at Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore. His lab develops new tools to better understand and manipulate T cell responses to infectious disease, cancer, and autoimmunity. They hope these tools and insights will lead to the next generation of immunotherapies.