Programming the immune system to supercharge cancer cell therapies
Genome-wide approaches to engineer more effective anti-cancer
immunotherapy

Date:
March 16, 2022
Source:
New York Genome Center
Summary:
Scientists have developed a genetic screening platform to identify
genes that can enhance immune cells to make them more persistent
and increase their ability to eradicate tumor cells.



FULL STORY ==========================================================================
The first FDA-approved gene therapies are living drugs: immune cells
taken from cancer patients engineered to target tumor cells. However, for
many patients, these advanced therapies do not result in a long-lasting remission. Now, scientists at the New York Genome Center and New York University have developed a genetic screening platform to identify genes
that can enhance immune cells to make them more persistent and increase
their ability to eradicate tumor cells.


==========================================================================
In the journal Nature, the researchers describe the discovery of synthetic
gene programs that profoundly rewire a specific kind of immune cell
called T cells, making them more effective at finding and fighting cancer cells. The research team, led by Neville Sanjana, PhD, Core Faculty Member
at the New York Genome Center, Assistant Professor of Biology at New
York University, and Assistant Professor of Neuroscience and Physiology
at NYU Grossman School of Medicine, profiled the impact of nearly 12,000 different genes in multiple T cell subsets from human donors. The goal
of this large-scale genetic screen was to identify precisely those genes
that enable T cells to proliferate and to understand how those genes
impact other aspects of immune cell function relevant to fighting cancer.

Previous efforts to engineer T cells have focused on the targeting of
specific tumor types by careful selection of cancer or tissue-specific
proteins (antigens). Since first developed more than 30 years ago,
chimeric antigen receptor (CAR)-T cell therapy has proven highly effective
in targeting blood cancer cells, resulting in multiple FDA-approved
CAR-T therapies. CAR-T cells have antigen receptors on their surface
that recognize specific proteins present on cancer cells to target and
destroy them. Some patients are cancer free even a decade after their
CAR-T cell therapy, as the T cells introduced years earlier are still
doing their job. But one of the major challenges facing biomedical
science is to understand why a large majority of cancer patients who
receive CAR-T cells fail to achieve lasting remission.

Dr. Sanjana, senior author of the study, explained, "To date, genetic engineering of T cells has been focused on finding new antigens or new
CARs. We took a radically different approach: Instead of changing the
antibody, we thought why not try adding genes that transform T cells
into more aggressive cancer fighters? These modifier genes worked very
well in blood cancers, and we believe they will likely work for multiple antigens and in solid tumors." By combining modifier genes identified
in the screen with existing CARs, the researchers were able to engineer T
cells that were more effective at eliminating tumor cells. One particular modifier gene, lymphotoxin beta receptor (LTBR), acts like a molecular
fountain of youth: with LTBR, T cells multiply, have a greater proportion
of younger, more stem cell-like cells and resist becoming exhausted
over time. Adding LTBR also caused T cells to secrete more cytokines,
which are vital for the anti-tumor activity of T cells.

Cytokines play an essential role in enabling T cells to better communicate
with other immune cells in the body and launch coordinated attacks on
the cancer.

Interestingly, LTBR is not normally expressed in T cells, which
highlights the power of the genome-scale screen to find genes that
activate completely new cellular programs.

"Our goal was to take existing immunotherapies and make them better. We
were astonished that LTBR so significantly potentiates CAR therapies. It
is an important step forward towards the development of next-generation
CAR-T cell therapy," said the study's first author Mateusz Legut, PhD,
a postdoctoral fellow in the Sanjana Lab. The research team found that
adding LTBR rewires the genome of T cell, triggering expression of many
other genes that potentiate T cell function. The team was able to quickly understand the effects of LTBR and similar modifier genes by combining
gene overexpression screens with single- cell genomics. The new method
that they developed -- OverCITE-seq -- allowed the researchers to test
the impact of different modifier genes on the cellular states of T cells,
which includes the expression of every gene, the proteins decorating the
cell surface, and the unique T cell receptors expressed by each cell (clonotype). OverCITE-seq gave the researchers a detailed picture of
how each modifier gene boosts T cell activity and did so for all of the top-ranked genes in one single-cell experiment. For LTBR, this yielded
an early clue that a large number of genes were changing, leading
the researchers to further identify a well-studied modulator of gene
expression called NF-kB driving many of these changes. This LTBR-driven profound reprogramming was also seen in so- called unconventional T
cells such as ?? T cells, which are present at a lower abundance than conventional T cells but can target a more diverse set of tumors.

"The most exciting aspect is the demonstration that LTBR and other
highly ranked genes improved the antigen-specific responses of chimeric
antigen receptor T cells and ?? T cells. If validated in vitro and in
clinical testing, this may have profound implication for future CAR-T
cell therapies in both lymphoid malignancies and other cancers." said
study co-author Catherine Diefenbach, MD, an Associate Professor in
the Department of Medicine at the Grossman NYU School of Medicine and
the Director of the Clinical Lymphoma Program at NYU's Perlmutter
Cancer Center. The team also combined several top- ranked genetic
modifiers with CARs similar to two existing FDA-approved therapies for
blood cancers: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). Virtually all modifiers tested boosted CAR-T responses,
including LTBR. Since T cells from cancer patients tend to be in poor
condition compared to T cells from healthy donors, the researchers wanted
to also test LTBR's ability to rejuvenate cancer patient T cells. They
added LTBR together with a CAR to dysfunctional T cells from patients
diagnosed with diffuse large B cell lymphoma, a blood cancer, and found
a similar boost in T cell function, suggesting that the technology could
work as an optimized therapy in the clinic.

Andrew Sewell, PhD, an expert in T cells and immunotherapy from Cardiff University's School of Medicine who was not involved in the study noted,
"Gain- of-function screening in T cells has great potential to uncover how
to make immunotherapies more successful -- especially in solid cancers
where current CAR T cell therapies do not work well." The research team
also showed that T cells enhanced with modifier genes were better able
to eradicate not only leukemia but also pancreatic cancer cells. Those
results are encouraging not only to develop a larger panel of enhanced
CAR-T therapies for blood cancers, but for the key role they could play
in targeting solid tumors, a field in which establishing efficient CAR-T immunotherapy has been more challenging.

In addition to Drs. Legut, Diefenbach and Sanjana, the research team
included co-authors from the Sanjana lab, the NYGC Technology Innovation
Lab, and the lab of Teresa Davoli, PhD, at the NYU Grossman School
of Medicine. The Sanjana Lab has been focused on developing new gene
editing and functional genomic technologies to reduce the high failure
of current immunotherapies and build next-generation therapeutics. Since
the newly-characterized modifier genes like LTBR can work hand in hand
with already approved CAR-T therapies, this research has clear potential
to move from bench to bedside and improve outcomes for cancer patients
around the world.

Video: https://vimeo.com/687951684

========================================================================== Story Source: Materials provided by New_York_Genome_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mateusz Legut, Zoran Gajic, Maria Guarino, Zharko Daniloski,
Jahan A.

Rahman, Xinhe Xue, Congyi Lu, Lu Lu, Eleni P. Mimitou, Stephanie
Hao, Teresa Davoli, Catherine Diefenbach, Peter Smibert, Neville
E. Sanjana. A genome-scale screen for synthetic drivers of T cell
proliferation.

Nature, 2022; DOI: 10.1038/s41586-022-04494-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220316132655.htm

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