Post originally written March 2nd, 2015
$KITE Some thoughts on today’s announcement on neo-antigen targeted TCRs.
First, I do not study cancer immunology, but I enjoy following &
learning about different therapeutic approaches, and approaches such as
adoptive transfer of T-cells are very interesting.
Kite Pharma today announced they are expanding their CRADA with the NCI
to work on developing T-cell receptor (TCR) product candidates that are
designed to target neo-antigens specific to each patient’s tumor. This
is a fundamentally different approach from the current wave of TCR
product candidates currently being developed by $JUNO or $KITE.
I would break down the current wave of TCRs targets into 3 different
types of aberrant protein expression, which are thus visible to T-cells
through recognition of new peptide-MHC complexes. The first type is
targeting the overexpression of a protein in the tumor tissue, such as
WT-1. The second type is targeting the re-expression of a protein that
is normally restricted in expression to the immune-privileged testis –
the so-called cancer-testis antigens, such as NY-ESO-1. The third type
is targeting the expression of a viral protein from a virus that is
associated with tumorigenesis, such as HBV or EBV viral proteins.
While the aberrant expression of these different classes of proteins all
provide potential targets for TCRs, there is increasing evidence that
the endogenous T-cell response against the tumor is actually against
neo-antigens, which are produced by the processing of proteins that are
mutated specifically in the tumor. This is supported by the observation
that Tumor Infiltrating Lymphocytes (TILs), which have also been used as
an adoptive T-cell therapy, react against neo-antigens specific to
tumor mutations: http://www.ncbi.nlm.nih.gov/pubmed/23690473, http://www.ncbi.nlm.nih.gov/pubmed/23644516.
Additionally, it is believed that the T-cells that are reactivated by
checkpoint blockade, such as PD-1 antibodies, also are reacting against
From the press release from Kite, it appears they will explore making
neo-antigen specific TCRs, most likely using something similar to
workflow C in the figure posted in the previous tweet. This figure comes
from a very nice review of TCR, CAR-T & TIL approaches, which is
publicly available & I would definitely suggest a read: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920180/
This means that each patient would get a TCR product that is unique to
that patient in the sequence and specificity of the TCR transduced into
their T-cells. To me, this seems like a potentially daunting
Workflow A has actually already been applied, quite successfully, in a
single patient, and this was published in Science last year: http://www.sciencemag.org/content/344/6184/641
As far as I know, no data has ever been published on a patient(s) being
treated by workflow C, so we’ll have to see how this approach actually
plays out. I would keep an eye out for further publications from
Rosenberg’s group, as they might publish on further developing this
So why add the extra steps of identifying the TCR sequence and
generating viral constructs to make TCR-modified T-cells as opposed to
just using a mixture of TILs or purifying a specific TIL population, as
in workflow A?
It’s not entirely clear to me what the advantages or disadvantages would
be, but here is a list of few that I could think of, influenced by some
mentioned in this other review from Rosenberg & colleagues:
Potential advantages of putting TCRs into T-cells vs. just using TILs:
Unique to TCRs:
1. Can put the TCR into a given T-cell population (T-cells are
heterogeneous, and some populations may be better for adoptive t-cell
therapy than others).
2. Can increase TCR affinity for the antigen, but this could decrease specificity
3. Potentially don’t need as many tumor-reactive t-cells to identify
& clone the TCR & put this into patient T-cells → it is possible
this may improve the ability to grow a T-cell product, as a TIL product
suitable for use was only able to be generated from ~55% of patients
with metastatic melanoma: http://clincancerres.aacrjournals.org/content/17/13/4550.full
4. Potentially already have scalable production method for TCR-modified
T-cells that this workflow would feed into after a number of additional
Can be done with TILs (but requires different/extra steps, like workflow A):
1. With TCRs, you know characteristics of the receptor you put in &
have a pure population of T-cells with the defined receptor → for TILs,
you can achieve something similar by selecting TILs with a certain
reactivity, as was done in Rosenberg group’s previously mentioned
Science paper: http://www.sciencemag.org/content/344/6184/641
2. Can engineer other properties into the T-cell, such as secretion of
cytokines, provide co-stimulation, prevent apoptosis, prevent
immunosuppression (knockout PD-1) etc. These modifications could also be
made directly in TILs as well, but again, you would be starting from a
different population of cells.
Potential disadvantages to generating patient specific TCRs vs. TILs:
1. Only targeting one antigen at a time, so might be easy for selection
of tumor cells that lack that antigen – especially true if the antigen
is simply a passenger mutation & not driving tumorigenesis (many
neo-antigens are probably just passengers). Passenger mutations would
likely cost little for the tumor to lose them.
Potential advantage or disadvantage – manufacturing:
If you look at the figure posted in the previous tweet, showing the
workflow of the different approaches to generating neo-antigen reactive
T-cells, you can see you are adding a number of potential steps after
the common step of identifying tumor-reactive T-cells. You have to
generate single-cell T-cell clones, sequence the TCR & generate a
new TCR retro/lenti viral construct to insert this into T-cells isolated
from the patient (at this point it is the same as any other TCR product
preparation). Making this feasible at a large enough scale is
potentially the biggest challenge to this therapeutic approach.
In conclusion, I really like the approach of targeting tumor
neo-antigens, these can serve as kind of a fingerprint of the tumor, as
they are specific to the mutations the tumor has accumulated.
Additionally, it is clear that the immune system can recognize
neo-antigens. It will be interesting to see what approaches emerge as
the best ways to generate an immune response against neo-antigens. I’d
be happy to discuss more if anybody else is interested.
Welcome to Biotechr
Biotechr is written by Dr. Robert Kruse (@RobertLKruse), who holds a PhD and is currently completing his MD. His research work focused on infectious disease and immunology. This blog is focused on analyzing the latest developments in biotechnologies being developed in academia and industry, with a particular focus on biomedical therapeutics. I hope that the posts are interesting and useful, and hope you join in the discussion with guest posts on the site!
Disclaimer: The thoughts on this blog are not intended as any investment advice regarding any companies that might be discussed, and represent my opinion and not the opinions of my employer. This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual.