Multiplexing Phenotype and Function for More Biologically Relevant Insights - 37

Related Article from
The advantages conferred by DAP10 were summarized by Dr. Sotiropoulou as
follows: "We have a first-generation CAR that acts like a second-generation CAR,
providing the first and second signal, rendering the cell effective to kill the tumor
cell and provide cytokines."
Although the CAR T cells themselves don't seem to persist, a long-term antitumor
activity was observed in mouse models. "These CAR T cells modulate the microenvironment and boost the immune system of the host so that you can have an immunological memory," Dr. Sotiropoulou asserted. Having demonstrated some efficacy and
a good safety profile in low-dose clinical trials for hematological cancers, CYAD-01 is
currently in a dose escalation trial for several different solid and liquid tumors.
Switching from CARs to TCRs
In a panel discussion, Robert Hofmeister, Ph.D., chief scientific officer of TCR2
Therapeutics, talked about the need to accessorize CAR T cells with more costimulatory molecules and to increase the expression of cytokines, "just to help the
CARs over a certain hurdle, to be active in the suppressive immune environment."
Traditional CARs are artificial constructs, making use of only the ζ chain of the entire
eight-subunit T-cell receptor (TCR) complex, and "that leads to inadequate activation
of the cell, which probably translates into a lack of persistence in patients and also a
lack of activity."

He sees the field pivoting away from CARs and toward the use of engineered TCRs
to combat solid tumors. Yet TCRs are human leukocyte antigen (HLA)-restricted,
meaning that they will recognize antigen only in the context of a given HLA-and
different people carry different HLAs. "This is a major drawback when it comes to
recruitment of patients," Dr. Hofmeister insisted.
TCR2 has developed a hybrid platform called TRuC that utilizes the entire TCR
complex to drive T-cell activation, yet is independent of the HLA. "We tether an
antibody-binding domain to one of the TCR subunits (in the lead program, we
tether it to the ε chain) ... which gets integrated into the natural TCR complex," he
explained.
In animal studies, the TRuC cells showed maximal efficacy against tumors as well as
long persistence. With TRuC cells, Dr. Hofmeister added, "we don't get the massive
overshooting of cytokines [cytokine release syndrome] that you observe with CAR T
cells."
TCR2 Therapeutics has developed TRuC, which stands for T cell Receptor fUsion
Construct. According to the company, TRuC is the first engineered T-cell platform to
use the complete T-cell receptor (TCR) complex without the need for human leukocyte antigen (HLA) matching. By conjugating tumor antigen binder (for example,

TCR2 Therapeutics has developed TRuC, which
stands for T cell Receptor fUsion Construct.
According to the company, TRuC is the first
engineered T-cell platform to use the complete
T-cell receptor (TCR) complex without the need
for human leukocyte antigen (HLA) matching. By
conjugating tumor antigen binder (for example,
scFV, sdAb, Fab) to the TCR complex, the TRuC
construct can recognize highly expressed surface
antigens on tumor cells without HLA and employ
the complete TCR machinery to drive the totality of
T-cell functions required for tumor killing.

37

| January, 2019


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Multiplexing Phenotype and Function for More Biologically Relevant Insights

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