Novel Dual CAR T cell immunotherapy holds promise for targeting the HIV reservoir

Date:
August 31, 2020
Source:
Massachusetts General Hospital
Summary:
A recent study describes a new Dual CAR T cell immunotherapy that
can help fight HIV infection.



FULL STORY ==========================================================================
A recent study published in the journal Nature Medicine, led by
researchers Todd Allen, PhD, a professor of Medicine at Harvard Medical
School (HMS) and group leader at the Ragon Institute of MGH, MIT and
Harvard, and Jim Riley, PhD, a professor of Microbiology in the Perelman
School of Medicine at the University of Pennsylvania, describes a new Dual
CAR T cell immunotherapy that can help fight HIV infection. The paper's
first authors are Colby Maldini, a graduate student at the University
of Pennsylvania and Daniel Claiborne, PhD, a research fellow at the
Ragon Institute.


========================================================================== "This study highlights how relatively straightforward alterations to the
way T cells are engineered can lead to dramatic changes in their potency
and durability," Riley said. "This finding has significant implications
for using engineered T cells to fight both HIV and cancer." The global
HIV epidemic impacts more than 35 million people around the world.

Antiretroviral therapy (ART) is a daily treatment that can control,
but not cure, HIV infection. However, access and lifelong adherence to a
daily regimen is a significant barrier for many people living with HIV. A
major hurdle to HIV cure is the viral reservoir, copies of HIV hidden
away in the genome of infected cells. If ART treatment is stopped, the
virus is able to rapidly make new copies of itself, ultimately leading
to the development of AIDS.

CAR T cells are a powerful immunotherapy, currently used in cancer
treatments, in which a patient's own immune T cells are engineered to
express Chimeric Antigen Receptors (CARs). These CARs re-program the T
cells to recognize and eliminate specific diseased or infected cells,
such as cancer cells or, potentially, HIV-infected cells.

Allen's and Riley's research groups worked together to design a new HIV- specific CAR T cell. They needed to design a CAR T cell that would be
able to target and quickly eliminate HIV-infected cells, survive and
reproduce once in the body, and resist infection by HIV itself, since
HIV's primary target is these very same T cells.

"By using a stepwise approach to solve each issue as it arose,
we developed protected Dual CAR T cells, which provided a strong,
long-lasting response against HIV-infection while being resistant to
the virus itself," Allen said.

This Dual CAR T cell, a new type of CAR T cell, was made by engineering
two CARs into a single T cell. Each CAR had a CD4 protein that allowed it
to target HIV-infected cells and a costimulatory domain, which signaled
the CAR T cell to increase its immune functions. The first CAR contained
the 4-1BB co-stimulatory domain, which stimulates cell proliferation
and persistence, while the second has the CD28 co-stimulatory domain,
which increases its ability to kill infected cells.

Since HIV frequently infects T cells, they also added in a protein called
C34- CXCR4, developed in the lab of James Hoxie, MD, a professor of
Hematology- Oncology at Penn. C34-CXCR4 prevents HIV from attaching to and
then infecting the cell. The final CAR T cell was long-lived, replicated
in response to HIV infection, killed infected cells effectively, and
was partially resistant to HIV infection.

When the protected Dual CAR T cells were given to HIV-infected mice,
the team saw slower HIV replication and fewer HIV infected cells than in untreated animals. They also saw reduced amounts of virus and preservation
of CD4+ T cells, HIV's preferred target, in the blood of these animals. In addition, when they combined Dual CAR T cells with ART in HIV-infected
mice, the virus was suppressed faster, which led to a smaller viral
reservoir than in mice who were only treated with ART.

"The ability of these protected Dual CAR T cells to reduce the HIV burden
in a variety of tissues and cell types, including long-lived memory CD4+
T cells, we believe supports the approach of using CAR T cell therapy
as a new tool to target the HIV reservoir towards a functional cure for
HIV," said Allen.


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


========================================================================== Journal Reference:
1. Colby R. Maldini, Daniel T. Claiborne, Ken Okawa, Tao Chen,
Derrick L.

Dopkin, Xiaochuan Shan, Karen A. Power, Radiana T. Trifonova,
Katharine Krupp, Meredith Phelps, Vladimir D. Vrbanac, Serah Tanno,
Timothy Bateson, George J. Leslie, James A. Hoxie, Christian
L. Boutwell, James L. Riley, Todd M. Allen. Dual CD4-based CAR T
cells with distinct costimulatory domains mitigate HIV pathogenesis
in vivo. Nature Medicine, 2020; DOI: 10.1038/s41591-020-1039-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200831154350.htm

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