A couple disclaimers before proceeding:
1) I own a tad of stock in two of the below-mentioned companies (Gritstone Oncology and Genocea Biosciences).
2) My historical stock-picking record is probably not so different than monkeys throwing darts at a list of candidates. Possibly worse.
Despite the above, I’m excited about a narrow field of
research, that of neoantigen cancer vaccines. For intimate details on the
subject, you can check out a wonderful review here. There may be some bias in that “wonderful”
appraisal. In brief, researchers have long sought druggable targets that are
unique to cancers, not healthy tissue. Historically, such targets have been
elusive. However, we now realize the following:
1) Cancers often have a lot of mutated DNA.
2) A decent % of these mutations are represented in
the form of mutated proteins.
3) A decent % of mutated proteins get chopped up
into little bits, and these bits (specifically, 8-11 amino-acid peptides) get
“displayed” on the outside of cells. These are “neoantigens.”
4) A certain % of these displayed peptides are
recognized by the immune system as foreign.
5) Of these, some have the potential to trigger an
anti-cancer immune response.
6) Clinical introduction of these peptides has
provoked profound responses in some cases.
Of course, the above steps simplify the subject and make it
sound easy. If you have any background in molecular biology, you’ll recognize
that it’s a hell of a lot of work to get to step #6. Specifically, you’ll do
exome sequencing, RNA-seq, possibly mass spectrometry and/or ribosomal
profiling, and a lot of bioinformatics to arrive at a list of peptide
candidates. Inject the peptides into the patient, and they may fail to
stimulate the real immune system despite your high-tech tetramer assays. All of
this work must be done fast, as the cancer grows and spreads in the patient’s
body.
Genocea (GNCA) claims that your hard-earned peptide
candidates may actually inhibit an immune response. This is a unique claim,
prompting GNCA to create a name for such neoantigens: “inhibigens.” You can
read GNCA’s recent, high-impact paper on the subject here. GNCA goes further, saying that some common
assumptions in the field may be misguided; specifically, GNCA minimizes notions
that peptide-HLA-binding affinity is strongly relevant to an immune-triggering
effect (“immunogenicity”) and that “exotic” neoantigens, generated by events
like gene fusions, aberrant splicing, translation of supposedly “non-coding”
RNA (etc.), would be especially potent candidates.
GNCA can make these claims because it takes a step nobody
else seems interested in: assaying every possible neoantigen candidate
(potentially hundreds) from a patient for likely immunogenicity, rather than
making the aforementioned assumptions to whittle down the candidate list to,
say, 5 neoantigens. You can go to GNCA’s website to check out various
presentations and the clinical status of its offerings (in brief: there’s
nothing in phase III and no overtly amazing results as yet).
What I like here is that if GNCA is correct, the competition
may be significantly handicapped. Meanwhile, GNCA accumulates real-world data
on the parameters that really provoke the immune system, with a minimum of bioinformatic
whittling. The stock may go to zero, get bought out, or skyrocket…I doubt it’ll
tread water for the next 5 years.
Gritstone (GRTS) offers a more conventional approach to
neoantigen generation, but they seem to be the most prominent and advanced
“pure play” in the field. Until January, the company quietly advanced its
neoantigen programs for cancer. That changed with the announcement of a
Gates-Foundation sponsored program to use the underlying technology to discover
and target Covid-related antigens (why not...these foreign peptides also get
displayed on the surface of cells and provoke immune reactions), causing the
stock to quadruple overnight. Another recent announcement involves an
HIV-related collaboration with biotech biggy Gilead. The stock has come down to
earth since January.
Gritstone’s potential edge derives largely from its method
of using AI and bioinformatics to deconvolute big datasets to arrive at optimal
neoantigen candidates. See GRTS’s own high-impact paper here. In addition to purely “personal”
treatments, the company is also testing “off the shelf” peptides that are found
in the most commonly mutated proteins in cancer. This sounds like a no-brainer,
but cancers often weed out the mutated peptides that provoke strong reactions.
Both the personalized and off-the-shelf products are in clinical trials, with
intriguing early results. Again, for results and presentations, check out the website.
If GNCA and/or GRTS are lacking in any of the attributes
that you seek in a biotech, you could also check out Agenus (AGEN), Achilles
(ACHL), Personalis (PSNL), Vaccibody (VACC; Oslo stock exchange), or Instil (TIL). We note that one of the early neoantigen companies,
Neon Therapeutics, was bought out in January of 2020 by Biontech (BNTX), which
is now famous for its Covid-19 mRNA vaccine; the big guys are watching these
entities. Moderna, in collaboration with Merck, is also in the field. A couple academic and private companies also have a stake in the future of neoantigen vaccines. Check out table 2 in a very recent, comprehensive review to get a sense of where neoantigen clinical trials stand at the moment.
In theory, proper neoantigen candidates should not provoke
any reaction to healthy tissue. They’re just short peptides (or the RNA that
codes for them, as in mRNA vaccines) that are already found in cancers, not
entirely novel molecules that need to be carefully studied for toxicity in a
number of tissues. I expect that the FDA will quickly adapt to the fact that
these personalized peptides are generally benign once the positive data starts
flowing at a high rate. Nevertheless, the market may be viewing neoantigen
vaccine companies as typical biotechs, with narrow-target drugs that take 8 or
more years, and billion dollar expenditures, to receive approval; there’s an opportunity here.
For future reference, GNCA and GRTS are now priced at $2.21 and $8.64.
***
Users of the WhatIsMyGene database might be interested to
know that, whenever possible, we make note that a particular dataset was
contributed by a biotech company (as opposed to most studies in the database,
which derive from academic institutions). Thus, you can open the “relevant
studies” app, enter “Syros” (for Syros Pharmaceuticals) and see a list of
studies relevant to their drug candidates. You can then test these datasets
against the entire database with the “Fisher” app and get a sense of what the
drug candidate actually does. Of course, many biotechs keep data solely
in-house, seeing secrecy as more important than the exposure that could result
from a high-impact publication. Other times, biotech-relevant data may be
published by an entity that appears purely academic. If you see a case where
we’ve missed the fact that a biotech is behind a particular dataset, let us
know!
