At a glance:
- By ROBERT LEVY | Dana-Farber
- Research pinpoints the source of immune cell exhaustion that may interfere with the efficacy of CAR-T treatments for cancer.
- The study reveals that specific groups of proteins regulate immune cells' ability to sustain key functions.
- Discovery opens the door to new therapeutic approaches that prevent T cell therapies from losing potency over time.
Custom-made to attack cancer cells, CAR T-cell therapies have opened a new era in the treatment of cancer, particularly blood cancers. The approach involves extracting a patient's own T cells and modifying them in the lab to make them better at spotting and killing tumors.
Yet, all too often, these optimized CAR-T cells display a frustrating trait inherited from the original immune cells: a drastic loss of cancer-fighting fervor known as "T-cell exhaustion," which can also affect how immune cells respond to other problems such as viral infections.
This vexing lapse into listlessness has diminished the effectiveness of CAR T-cell therapies in some patients and prompted scientists to find its source.
Now, Harvard Medical School researchers at Dana-Farber Cancer Institute and colleagues at the NYU Grossman School of Medicine have done just that.
In a study published March 20 in Molecular Cell, the scientists report they have elucidated the commanding role of a specialized group of proteins in the nuclei of our cells. These proteins, called mSWI/SNF (or BAF) complexes, have important functions - to both activate T cells and trigger their exhaustion.
The discovery suggests that targeting these complexes, either by gene-cutting technologies such as CRISPR or with small-molecule drugs, could reduce exhaustion and give CAR T cells, and, in general, all tumor- or infection-fighting T cells, the staying power to carry out their functions for longer.
"CAR T cells and other therapies made from living cells have enormous potential in treating cancer and a range of other diseases," said the study's senior author, Cigall Kadoch, HMS associate professor of pediatrics at Dana-Farberand the Broad Institute of MIT and Harvard. "To reach that potential, however, the field had wrestled with the problem of exhaustion. Our findings in this study indicate new, potentially clinically actionable ways of addressing this."
CAR (chimeric antigen receptor) T cells are made by collecting thousands of cells from a patient's own immune system and equipping them with features that help them latch onto and destroy cancer cells. After the modified cells reproduce into the millions, they are injected back into the patient, where they strike at cancer cells.
"The problem is that most engineered T cells, like CAR T cells, tire out," said study co-first author Kimberlee Hixon, a graduate student in the biological and biomedical sciences doctoral program at HMS. "T cells become activated, just as normal T cells in our body do when they encounter infection or other triggers, but they soon after stop dividing and fail to properly attack their targets."
Research over the years has suggested that exhaustion, as well as activation and the acquisition of memory-like features, are not controlled by a single gene or a few genes, but by the coordination of many genes that together generate an exhaustion "program" for the cell.
Kadoch and her colleagues began homing in on mSWI/SNF complexes years ago as potential regulators of these programs. These complexes, the focus of the Kadoch Laboratory, are large molecular machines that glide along the genome like cursors on a line of text. Where they stop, they can open up DNA strands, switching on genes in that area, and where they disappear from results in the closing of DNA and the shutting off of those genes.
Such complexes qualify as the kind of master switch that could potentially control the exhaustion program. Kadoch and her team decided to track these patterns over the entire course of T-cell activation and exhaustion to determine where they are situated on the genome of battle-ready T cells and how those positions change as exhaustion sets in.
"We pursued a very comprehensive profiling effort to identify the genomic localization of these complexes in T cells across time, in both mouse and human contexts, Kadoch said. "We found that they move around in a state-specific manner, which raises the question of why they move and how they know where to go in each state."
The biggest influences on their location, it turned out, were certain transcription factors, proteins critical to activating highly specific sets of genes. The factors guide mSWI/SNF complexes and steer them to precise sites on the genome.
"At each stage of T-cell activation and exhaustion, a different constellation of transcription factors appears to guide these complexes to specific locations on the DNA," Kadoch said.
As this profiling work was underway, co-senior author Iannis Aifantis and his colleagues at the NYU Grossman School of Medicine were systematically shutting down genes in T cells to see which ones, when silenced, slowed or stopped the process of exhaustion.
"We found that all the top hits in our screen - the genes whose inhibition had the greatest impact on exhaustion - encoded the very mSWI/SNF complexes central to Cigall's lab," Aifantis said. "Our labs then together performed a detailed series of joint experiments that showed that if you stifle the genes encoding various components of these complexes, the T cells not only don't get exhausted, but proliferate even more than before."
The two labs followed up these findings by employing a group of newly developed small molecule inhibitors and degraders targeting mSWI/SNF complexes. They found that in response to these inhibitors, genes that promote cell exhaustion became less active while those that spur activation became more active. "We essentially reversed the exhaustion program with these inhibitors," Kadosh said, "and resulting cells resembled more memory-like and activated T cell features."
The findings are especially timely given that the first compounds that specifically inhibit the catalytic activity of mSWI/SNF complexes are now being tested in patients in phase 1 clinical trials for cancer. Experiments in animal models of melanoma, acute myelogenous leukemia, and other settings hint at the promise of such compounds. In addition to favorable changes in T cells, when the groups treated animals with T cells that had been exposed to mSWI/SNF inhibitors, tumor growth was reduced.
"We are very excited by these findings on numerous fronts, from identifying another important example of the wide repertoire of mSWI/SNF functions in human biology, to the opportunity to target these functions to improve immunotherapeutic approaches for the treatment of cancer and other conditions," said Kadoch. "We have a lot more to do, but this work provides an important new foundation."
Authorship, funding, disclosures
Co-first authors are Elena Battistello, of the Perlmutter Cancer Center, NYU Grossman School of Medicine, and Kimberlee Hixon and Dawn Comstock, of Dana-Farber and the Broad Institute. Additional co-authors included W. Nicholas Haining and Jun Qi, of Dana-Farber; Clayton K. Collings, Kasey Cervantes, and Madeline Hinkley, of Dana-Farber and the Broad Institute; Xufeng Chen, Javier Rodriguez Hernaez, Soobeom Lee, Konstantinos Ntatsoulis, and Aristotelis Tsirigos, of the Perlmutter Cancer Center at NYU; Kathryn Hockemeyer, of the Perlmutter Cancer Center at NYU and Dana-Farber; Annamaria Cesarano and Fabiana Perna of Indiana University School of Medicine; and Matthew Witkowski, of the University of Colorado.
This work was supported in part by the National Institutes of Health (grants 1F31CA271427-0, 5F30CA239317, T32GM007753, T32GM144273, and 1DP2CA195762), the Switzerland National Science Foundation; the Lymphoma Research Foundation; the National Cancer Institute (grants 5R01CA173636, 5R01CA228135, 5P01CA229086, 5R01CA242020, 1R01CA243001, and 1R01CA252239); the Mark Foundation for Cancer Research Emerging Leader Award, and the Vogelstein Foundation. NYU Langone's Genome Technology Center is partially supported by the Cancer Center Support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
Kadoch is the scientific founder, scientific advisor to the board of directors, scientific advisory board member, shareholder, and consultant for Foghorn Therapeutics, Inc., and a member of the scientific advisory board and a shareholder of Nested Therapeutics and Nereid Therapeutics. She serves on the scientific advisory board for Fibrogen, Inc., and on the Molecular Cell editorial board, and is a consultant for Cell Signaling Technologies and Google Ventures. Aifantis is a scientific consultant for Foresite Labs and receives research funding from AstraZeneca Inc. Perna is an inventor on patents related to adoptive cell therapies, held by MSKCC (some licensed to Takeda), serves as a consultant for AstraZeneca, and receives research support from Lonza and NGMBio. Tsirigos is a scientific advisor to Intelligencia AI.
