IsoPlexis eBook - 13

Polyfunctional Strength Offers a New Approach to Defining Quality in Cell Therapy

much deeper understanding of exactly what is needed
and what you do not want to do in terms of highlighting
T-cell functions. A lot of those advances in understanding
are reflected in new generations of engineered CAR-T cells.
In fact, some of these new generations now represent the
pinnacle of cellular engineering.
GEN: Are all the CAR T-cells in the cell therapy product
created equally? What methods are currently being
used to determine the editing of these cells so that
they lead to the expected outcome?
Dr. Heath: Well, this issue of creating CAR-T cells equally is
something that has been refined only in the last year or two.
Very precisely engineered CAR-T cells are just now entering
the clinic.
Previously, maybe one used different retroviral vectors and
things like this to insert the CAR-T cell receptor, and it led to
a pretty high variability in CAR-T cells. One did not always
have great control where that receptor was inserted, and
so you might have ended up with a given CAR-T cell batch
that actually contained a host of different products from the
genetic point of view.
But now, more precise genome editing methods, such as
CRISPR, and the ability to insert genes as well as to remove
them, are narrowing that spectrum. Although they are not
in the clinic yet there are also a lot of efforts to try to develop
off-the-shelf CAR-T cells, in which one designs a CAR-T cell



product that can be used for almost any patient. These kinds
of things have evolved over the past few years so that the
unintended diversity in CAR-T cell manufacture is gradually
disappearing. Intended diversity, through engineering, will
continue to expand as scientists continue to invent.
GEN: At the other end of the spectrum, are there ways
to predict adverse responses to the CAR-T therapies?
Dr. Heath: There are some, but this is an area that is still
evolving. A key challenge is that there are many different types of CAR-T cells, and for any given type, we do not
have enough patients in clinical trials who exhibit specific
adverse responses to allow one to resolve the causes of
those responses. The diversity of CAR-T cell products that are
being introduced makes it challenging to do an apples-toapples comparison.
Some of the early, serious neurological events may have
been attributable to the variable properties of the CAR-T
cells, coupled with an incomplete knowledge of how diverse
patient populations might respond. But even then, the
number of those events was pretty low in frequency. For
example, when we looked at CAR-T cell products from Kite
Pharma a while back we saw that there were certain cytokines
that tended to precipitate neurological adverse events. Not
serious ones, but nevertheless they were real. We were able to
identify certain signatures in some of the CAR-T cell products
that seemed to correlate with those events, and we saw those
signatures before the CAR-T cells were given to the patient.

IsoPlexis eBook

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