Today (September 14) the Breakthrough Prize Foundation announced the recipients of the 2024 Breakthrough Prizes. Dubbed the “Oscars of Science,” the prestigious Breakthrough Prize recognizes outstanding contributions to science that advance our understanding and treatment of human disease. This year, three Life Sciences prizes were awarded to eight scientists whose research has transformed the treatment landscape from cancer to rare diseases.
Carl June, an immunologist at the University of Pennsylvania and Michel Sadelain, an immunologist at Memorial Sloan Kettering Cancer Center (MSKCC), received the Breakthrough Prize for the development of CAR T cell immunotherapy.
The third prize went to Thomas Gasser, a neuroscientist at the University of Tübingen, Andrew Singleton, a neurogeneticist at the National Institute on Aging, and Ellen Sidransky, a geneticist at the National Human Genome Research Institute for identifying risk genes for Parkinson’s disease.
As with many scientific breakthroughs in history, these discoveries are entrenched with stories of perseverance, serendipity, and convergence.
Pioneers of CAR T cell immunotherapy
T cells, foot soldiers of the immune system, express T cell receptors (TCR) that seek out and bind to antigens on cancer cells. This triggers an intracellular signaling cascade that prepares T cells for battle. For decades, the researchers in the labs of June, Sadelain, and others worked tirelessly to boost and hone T cells’ attacks. In recent years, the success of this innovative cell therapy treatment garnered much attention and acclaim, but it wasn’t always so.
Cell engineering was a nascent field when Sadelain joined Massachusetts Institute of Technology as a postdoctoral fellow in the early 1990s. Back then, researchers focused on the potential to correct genetic disorders and even considered introducing genes into cancer cells or hematopoietic stem cells, but not T cells. “The idea of putting genes in T cells was just perceived as being off the wall and unnecessary,” said Sadelain.
See also “New Insights to Improve CAR T Cells’ Safety”
For years, skepticism pervaded the field of immunology. In 1992, Sadelain presented his findings on the first genetically engineered T cell at a conference in Budapest. However, not many seemed interested in his findings.
Nevertheless, Sadelain persisted down this path, and he wasn’t alone. Zelig Eshhar, an immunologist at the Weizmann Institute, successfully fused the intracellular signaling domain cluster of differentiation three zeta (CD3ζ) with the antigen binding region of an antibody.1 The result was a synthetic receptor that honed its attack to cells expressing the target antigen.
These engineered receptors—today considered the first-generation CARs—improved T cells’ navigation system, but the cells soon ran out of gas. To overcome this, Sadelain and his team added a costimulatory domain to the synthetic receptor to further enhance the T cells’ attack.2 June’s team previously demonstrated that the costimulatory domain cluster of differentiation 28 (CD28) helps to regulate T cell function.3 When Sadelain expressed CD28 alongside CD3ζ and an antigen expressed on prostate cancer cells, he saw an amplified immune response.4
The addition of a costimulatory domain ushered in the second-generation CARs, which are used in all six approved CAR T cell therapies.
Since then, scientists tweaked the components to improve CAR navigational systems. Sadelain and his team modified their CAR design to target cluster of differentiation 19 (CD19), which is highly expressed on B cells.5 When they treated mice injected with Raji Burkitt lymphoma cells—a B cell malignancy—with their new and improved CAR, it protected the mice from developing a fatal hindlimb paralysis.
Despite the continued disinterest in the novel cell therapy, Sadelain, June and others moved forward with clinical trials. For this, the scientists needed to isolate T cells from patients’ blood, engineer the cells to express the CAR, and grow millions of cells in a dish before reintroducing the bolstered T cells to the patient. June’s team previously optimized cell culture methods for expanding human T cells in a dish, which was key to this advance.6 Few institutions, namely MSKCC, University of Pennsylvania, and the National Cancer Institute, had the facilities and capacity to produce the cell therapy.
In 2011, promising results from the first clinical trials trickled in and attracted the attention of researchers and biotech companies. Just six years later, the FDA approved the first CAR T cell therapy, Kymriah, for the treatment of acute lymphoblastic leukemia in certain pediatric and young adult patients.
CAR T cells revolutionized the field of cancer therapy, particularly for blood cancers. Last year, June and his colleagues at the University of Pennsylvania reported on the long-term remission of two patients with leukemia treated with CAR T cell therapy more than a decade ago.7
“It’s humbling, especially after so many years of having heard ‘Why bother?’” said Sadelain.
Novel treatments for cystic fibrosis
In 1989, scientists discovered the gene responsible for cystic fibrosis: cystic fibrosis transmembrane conductance regulator (CFTR).8 CFTR, a chloride ion channel, maintains an optimal balance of water and salts, and therefore the mucus, on the surface of the lungs. Over the next decade, scientists identified the protein product and how a mutation in the gene caused the CFTR protein to misfold.
In 2001, Van Goor, who had been studying ion channel biology in goldfish and rats, joined Negulescu’s team at Vertex Pharmaceuticals to work on treatments for cystic fibrosis. A year later, Hadida joined the team as the lead chemist.
With this misfolded protein, the problems are two-fold. First, most of the misfolded protein gets flagged and degraded. Second, the misfolded protein that successfully reaches the cell’s surface doesn’t function properly. The result is an imbalance in salt and water transport that leads to the characteristic sticky mucus that becomes a haven for pathogenic bacteria and viruses. “We knew from the very beginning that we needed to have two types of medicines,” said Van Goor.
See also “FDA Approves New Cystic Fibrosis Drug”
Cystic fibrosis is a multiorgan disease, so the team wanted to develop an oral small molecule that affects all of the organs in the body. “The problem then was, ‘Well how do you fix a misfolded protein?’ said Van Goor. “That problem took us 20 years to solve.”
The first step was to use high-throughput assays to screen thousands of molecules for ones that improved the function of misfolded CFTR in cultured cells.
After screening more than one million compounds, the trio managed to find a handful of chemical starting points. It then took years of medicinal chemistry optimization followed by clinical trials and regulatory approval timelines to turn these chemicals into medicines.9
As they anticipated, the team developed two types of CFTR modulators. While CFTR correctors ensure that more protein product gets rerouted from the cell trashcan to the cell surface, CFTR potentiators increase protein function at the cell surface.10 In 2012, the FDA approved Kalydeco, a CFTR potentiator monotherapy, following promising data from clinical trials showing benefits for a small percentage of patients that carry a CFTR mutation that affects ion channel opening.11
Approximately 90% of patients with cystic fibrosis carry at least one copy of the common F508del CFTR protein. Therefore, Van Goor and his team got to work exploring new drug combinations. In 2019, the FDA approved Trikafta, a three-drug combination of two CFTR correctors and one CFTR potentiator, for use in patients carrying one or two copies of the common F508del CFTR.12
Risk genes for Parkinson’s disease
In the 1990s, Sidransky studied Gaucher disease, a rare hereditary disorder wherein different mutations in the gene glucosylceramidase beta 1 (GBA1) cause a buildup in fatty substances in several organs, including the liver, spleen, and bone. “What fascinated me about [Gaucher disease] was the vast clinical heterogeneity that you see in a single gene disorder,” said Sidransky.
As a pediatrician studying a rare disease, Sidransky didn’t expect to find herself looking into Parkinson’s disease. However, early in her career, she noticed that several of her patients exhibited features typical of Parkinson’s disease, and that nearly 25% had family members with Parkinson’s disease.13,14
Sidransky said that the story might have ended there if it wasn’t for a serendipitous call from a former trainee who had brain tissue from a patient with a dual diagnosis of Gaucher disease and Parkinson’s disease. She shipped the samples to Sidransky, along with two Parkinson’s disease only samples, but the labels fell off in transport.
Unsure of which sample was which, Sidransky decided to measure the enzyme activity. “One was extremely deficient, but the other two were a lot lower than I expected,” said Sidransky.
She peered into the DNA. Lo and behold, one sample had two copies of the mutated GBA1 gene, but to her surprise the other two samples had single copies of GBA1 mutations. “This really blew us away,” said Sidransky. These data inspired her to analyze DNA from more than 50 postmortem brain samples from patients with Parkinson’s disease. She found that 12 patients who had Parkinson’s disease carried GBA1-related mutations.15
“Most neurologists didn’t really accept it. Even the geneticists couldn’t understand why—if it was that important—they didn’t pick up on it in their big GWAS studies.” Although evidence linking GBA1 to Parkinson’s disease was trickling in, it all came from small studies.
In a large, international collaboration study, Sidransky and her team collected around 10,000 DNA samples and mined through the data in search of GBA1 mutations.16 While two copies of the mutated gene led to Gaucher disease, the study revealed that one copy was a risk factor for Parkinson’s disease. In fact, patients with Parkinson’s disease were five times more likely to carry one of the two most common GBA1 mutations. “By then, I think the Parkinson’s disease community was pretty understanding that this was a really important risk factor,” said Sidransky.
See also “Is It Time to Rethink Parkinson’s Pathology?”
Although the exact mechanisms by which mutations in GBA1 increase disease risk still needed parsing out, subsequent work by Sidransky pointed to a faulty waste disposal system in the cell.17 Sidransky and her team found that reduced expression of the lysosomal enzyme glucocerebrosidase, encoded by GBA1, led to increased clumping of the protein alpha-synuclein, suggesting that impaired lysosomal clearance plays a role in pathophysiology.
Around this same time in 2002, Gasser and Singleton were on the hunt for genetic clues to Parkinson’s disease.
In contrast to Sidranksy’s journey starting from a single patient, they dove into thousands of patient samples. Their teams independently linkedmutations in the gene leucine-rich repeat kinase 2 (LRKK2) as a risk factor for the development of autosomal dominant Parkinson’s disease, a hereditary form of the disease.18,19 Since then, Gasser, Singleton, and others associated mutations in LRKK2 to disruptions in autophagic and lysosomal trafficking pathways.20
Scientists are currently investigating the therapeutic potential of drugs targeting these key players in the lysosomal system, including glucocerebrosidase, alpha-synuclein, and LRRK2 in clinical trials.
Reflecting on her work over the last three decades, Sidransky said, “It’s a great example of why we study rare diseases. We study them because it’s important for the rare disease community; we study them because they teach us important biology; and now we have an example of why studying rare diseases can give us a very unique porthole into common complex disorders.”
The Breakthrough Foundation will honor the 2024 laureates at a gala held in Los Angeles on April 13, 2024.
- Eshhar Z, et al. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. PNAS. 1993;90(2):720-724.
- Krause A, et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med. 1998;188(4):619-626.
- June CH, et al. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990;11(6):211-216.
- Maher J, et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat Biotechnol. 2002;20:70-75.
- Brentjens RJ, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. 2003;9:279-286.
- June CH. Toward synthetic biology with engineered T cells: A long journey just begun. Hum Gene Ther. 2014;25(9):779-784.
- Melenhorst JJ, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022;602:503-509.
- Riordan JR, et al. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-1073.
- Hadida S, et al. Discovery of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem. 2014;57(23):9776-9795.
- Van Goor F, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. PNAS. 2009;106(44):18825-18830.
- Accurso FJ, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Eng J Med. 2010;363:1991-2003.
- Keating D, et al. VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Eng J Med. 2018;379:1612-1620.
- Tayebi N, et al. Gaucher disease and parkinsonism: a pehnotypic and genotypic characterization. Mol Genet Metab. 2001;73(4):313-321.
- Goker-Alpan O, et al. Parkinsonism among Gaucher disease carriers. J Med Genet. 2004;41(12):937-940.
- Lwin A, et al. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004;81(1):70-73.
- Sidransky E, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Eng J Med. 2009;361:1651-1661.
- Aflaki E, et al. The complicated relationship between Gaucher disease and Parkinsonism: Insights from a rare disease. Neuron. 2017;93(4):737-746.
- Paisán-Ru??z C, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44(4):595-600.
- Zimprich A, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601-607.
- Taymans J-M, et al. Perspective on the current state of the LRRK2 field. NPJ Parkinsons Dis. 2023;9(1):104.