Vaccine delivers a boost to T cell therapy
The new strategy may enable engineered T cells to eradicate solid tumors
such as glioblastoma

Date:
July 5, 2023
Source:
Massachusetts Institute of Technology
Summary:
A new vaccine boosts the response of engineered CAR-T cells and
helps the immune system generate T cells that target other tumor
antigens. The researchers found this approach made it more likely
that a tumor can be eradicated in mice.


Facebook Twitter Pinterest LinkedIN Email

==========================================================================
FULL STORY ========================================================================== Engineering T cells to destroy cancer cells has shown success in treating
some types of cancer, such as leukemia and lymphoma. However, it hasn't
worked as well for solid tumors.

One reason for this lack of success is that the T cells target only one
antigen (a target protein found on the tumors); if some of the tumor
cells don't express that antigen, they can escape the T cell attack.

MIT researchers have now found a way to overcome that obstacle, using a
vaccine that boosts the response of engineered T cells, known as chimeric antigen receptor (CAR) T cells, and also helps the immune system generate
new T cells that target other tumor antigens. In studies in mice, the researchers found that this approach made it much more likely that tumors
could be eradicated.

"This vaccine boosting appears to drive a process called antigen
spreading, wherein your own immune system collaborates with engineered
CAR T cells to reject tumors in which not all of the cells express
the antigen targeted by the CAR T cells," says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT's departments of Biological Engineering and of Materials Science and Engineering, and a
member of MIT's Koch Institute for Integrative Cancer Research and the
Ragon Institute of MGH, MIT, and Harvard.

Irvine is the senior author of the study, which appears today in
Cell. The lead author of the paper is Leyuan Ma, a former postdoc at
the Koch Institute and currently an assistant professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine.

Engineered T cells The U.S. Food and Drug Administration has approved
several types of T cell treatments for blood cancers. These treatments
are based on CAR-T cells, which are engineered to display receptors that
can recognize a specific antigen found on cancer cells.

To try to adapt this kind of treatment to glioblastoma, a type of brain
cancer, researchers have designed CAR-T cells that target a mutated
version of the EGFR receptor. However, not all glioblastoma cells express
this antigen, and when attacked by CAR-T cells, some glioblastoma cells
respond by halting production of the target antigen.

In a 2019 study, Irvine and his colleagues enhanced CAR-T cells'
effectiveness against glioblastoma by delivering a vaccine to mice
shortly after the engineered T cells were administered. This vaccine,
which carries the same antigen targeted by the CAR-T cells, is taken up by immune cells in the lymph nodes, where the CAR-T cells are exposed to it.

In that study, the researchers found that this vaccine boost not only
helped the engineered CAR-T cells attack tumors, but it had another,
unexpected effect: It helped to generate host T cells that target other
tumor antigens.

This phenomenon, known as "antigen spreading," is desirable because
it creates populations of T cells that, working together, can fully
eradicate tumors and prevent tumor regrowth.

"That would be exactly the kind of thing that could help you deal with
the antigen heterogeneity of solid tumors, because if you primed host
T-cells to attack other antigens, they may be able to come in and kill
the tumor cells that your CAR-T cells cannot," Irvine says.

An immune boost In their new study, the researchers wanted to explore
how that additional T- cell response becomes activated. They used the
same type of CAR-T cells from their 2019 study, which are engineered
to target mutant EGFR, and the same vaccine. The mice in the study were
given two doses of the vaccine, one week apart.

The researchers found that in these boosted mice, metabolic changes
occurred in the CAR-T cells that increased their production of interferon gamma, a cytokine that helps stimulate a strong immune response. This
helps the T cells to overcome the immunosuppressive environment of the
tumor, which normally shuts down any T cells in the vicinity.

As the CAR-T cells killed tumor cells expressing the target antigen,
host T cells (not the engineered CAR-T cells) encountered other antigens
from those tumor cells, stimulating those host T cells to target those
antigens and help destroy tumor cells.

Without that host T cell response, the researchers found, tumors would
regrow even if the CAR-T cells destroyed most of the original tumor
cells. This happens because tumor cells treated with CAR-T cells often
stop producing the antigen targeted by the engineered cells, allowing
them to evade those cells.

Tumor eradication The researchers then tested their approach in mice with tumors that had different levels of the target antigen. They found that
even in tumors where only 50 percent of the tumor cells expressed the
target antigen, about 25 percent of the tumors could still be eradicated,
by a combination of CAR- T cells and host T-cells.

The success rate was higher for tumors with greater levels of the target antigen. When 80 percent of the tumor cells expressed the antigen targeted
by CAR-T cells, tumors were eliminated in about 80 percent of the mice.

The technology used in this study has been licensed to a company
called Elicio Therapeutics, which is working on developing it for
potential testing in patients. In this study, the researchers focused
on glioblastoma and melanoma, but they believe it could potentially be
used to combat other types of cancer as well.

"In principle, this should apply to any solid tumor where you have
generated a CAR T-cell that could target it," Irvine says.

The researchers are also working on ways to adapt CAR-T cell therapy so
that it can be used to attack tumors for which no targetable antigens
have been identified.

The research was funded by the National Institutes of Health, the Marble
Center for Cancer Nanomedicine at the Koch Institute, an ASPIRE Award
from The Mark Foundation for Cancer Research, an American Cancer Society postdoctoral fellowship, the Cell and Gene Therapy Collaborative at the Children's Hospital of Philadelphia, the W.W. Smith Charitable Trust, and
a Koch Institute Support (core) Grant from the National Cancer Institute.

* RELATED_TOPICS
o Health_&_Medicine
# Brain_Tumor # Cancer # Skin_Cancer # Stem_Cells
o Mind_&_Brain
# Hearing_Impairment # Dementia # Neuroscience # Anxiety
* RELATED_TERMS
o Monoclonal_antibody_therapy o T_cell o Immune_system o
Natural_killer_cell o BRCA1 o Brain_tumor o White_blood_cell
o Adult_stem_cell

==========================================================================

Print

Email

Share ========================================================================== ****** 1 ****** ***** 2 ***** **** 3 ****
*** 4 *** ** 5 ** Breaking this hour ==========================================================================
* Why_Birds_Ancestors_Lived;_Other_Dinosaurs_Died *
Dissolving_Cardiac_Device_Treats_Heart_Disease *
Webb_Locates_Dust_Reservoirs_in_Two_Supernovae *
Earth_Formed_from_Dry,_Rocky_Building_Blocks *
Ancient_Volcanic_Activity_On_Moon's_Dark_Side *
Highly_Conductive_Metallic_Gel_for_3D_Printing *
Potent_Greenhouse_Gas_Could_Be_Abated_Today *
Polymer_Brains_for_Artificial_Neural_Networks *
Early_Apex_Predator_Sought_Soft_Over_...

* Time_in_Universe_Once_Flowed_Five_Times_Slower

Trending Topics this week ========================================================================== HEALTH_&_MEDICINE Fitness Genes Cholesterol MIND_&_BRAIN Child_Psychology Creativity Educational_Psychology LIVING_&_WELL Fitness Healthy_Aging Staying_Healthy


==========================================================================

Strange & Offbeat ========================================================================== HEALTH_&_MEDICINE Grocery_Store_Carts_Set_to_Help_Diagnose_Common_Heart_Rhythm_Disorder_and Prevent_Stroke DNA_Can_Fold_Into_Complex_Shapes_to_Execute_New_Functions Everyone's_Brain_Has_a_Pain_Fingerprint_--_New_Research_Has_Revealed_for_the First_Time MIND_&_BRAIN
AI_Tests_Into_Top_1%_for_Original_Creative_Thinking Scientists_Discover_Spiral-Shaped_Signals_That_Organize_Brain_Activity Illusions_Are_in_the_Eye,_Not_the_Mind LIVING_&_WELL AI_Tests_Into_Top_1%_for_Original_Creative_Thinking Amputees_Feel_Warmth_in_Their_Missing_Hand Why_Do_Champagne_Bubbles_Rise_the_Way_They_Do?_Scientists'_New_Discovery_Is Worthy_of_a_Toast Story Source: Materials provided by Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Leyuan Ma, Alexander Hostetler, Duncan M. Morgan, Laura Maiorino,
Ina
Sulkaj, Charles A. Whittaker, Alexandra Neeser, Ivan Susin Pires,
Parisa Yousefpour, Justin Gregory, Kashif Qureshi, Jonathan Dye,
Wuhbet Abraham, Heikyung Suh, Na Li, J. Christopher Love, Darrell
J. Irvine. Vaccine- boosted CAR T crosstalk with host immunity
to reject tumors with antigen heterogeneity. Cell, 2023; DOI:
10.1016/j.cell.2023.06.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230705115136.htm

--- up 1 year, 18 weeks, 2 days, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)