Promising Personalized Approach to Liver Cancer Therapy Made Possible by DNA-based Neoantigen Research Designed at The Wistar Institute
April 30 2024 - 10:18AM
Promising Personalized Approach to Liver Cancer Therapy Made
Possible by DNA-based Neoantigen Research Designed at The Wistar
Institute
Hepatocellular carcinoma (HCC), or liver cancer, is an aggressive
malignancy with limited treatment options. An immunologically cold
cancer — meaning the tumors can effectively hide themselves from
the immune system — liver cancer can escape or not respond to
first-line treatment options, resulting in a poor prognosis. The
results of a new clinical trial published in Nature Medicine show
that a novel, personalized neoantigen vaccine therapy demonstrated
promising anti-tumor efficacy in patients with liver cancer who
failed their original front-line treatment. The foundational
biomedical research leading to this important study and important
outcome originated from research in the Vaccine & Immunotherapy
Center at
The Wistar Institute.
The clinical trial was directed by the Philadelphia
biotherapeutics company, Geneos Therapeutics — along with a
scientific team of collaborators including The Wistar Institute —
in the paper, “Personalized neoantigen vaccine and pembrolizumab in
advanced hepatocellular carcinoma: a phase 1/2 trial.”
Of the 36 participants enrolled, 34 were evaluable (i.e., able
to be studied under the trial guidelines) among these,
eleven demonstrated tumor regression by clinically
defined Response Evaluation Criteria in Solid Tumors (RECIST),
resulting in a tumor regression rate of 30.6% — supporting a
response to their therapy. Of those eleven, eight
had partial vaccine responses (meaning their tumors decreased in
size, with one such patient’s tumor shrinking enough to be
surgically removed), and three had complete responses — meaning
their observable tumors were eliminated. An additional 9 patients
exhibited stable disease under treatment. While not a direct
clinical endpoint, these patients' disease appeared to stop
progressing. The range for the median survival in months for
patients with liver cancer who have failed first-line therapy is
described as 12.9-15.1 months; however, the median overall survival
at the time of the study’s data cutoff was 19.9 months, with 17 of
the participants still being monitored for overall survival at the
time of publishing.
In context, the results support a significant increase in
survivorship for patients with this notoriously aggressive &
difficult-to-treat cancer compared to historical endpoints. Though
Phase 1/2 safety and efficacy studies are an important initial step
in clinical advancement of a new therapeutic, these notably
positive results open the possibility for additional research to be
conducted to evaluate the use of the team’s neoantigen vaccine in
expanded HCC cancer studies as well as to extend this technology to
additional cancers.
The host immune system has powerful immune surveillance
effectors termed “Killer T cells,” or CTLs, which serve to
eradicate foreign elements such as viruses growing in host cells by
killing the entire cellular factory. However, the ability to
recognize tumor antigens that are hiding in host cells is a much
more difficult task. Accordingly, as cancers grow, they can
overwhelm the host through increasingly rapid cell division, but
they also incorporate mutations or “mistakes” in multiple of the
cancer cells’ protein sequences, in part due to their bypassing
normal cell stringent regulatory processes. Those mutations
occurring in tumors' proteins are termed neoantigens (NeoAg):
proteins that are expressed uniquely in cancers as a by-product of
cellular dysfunction.
Geneos scientists worked with scientists in The Wistar Institute
Vaccine & Immunotherapy Center — led by David B.
Weiner, Ph.D., Wistar Executive Vice President,
Vaccine & Immunotherapy Center director, and W.W. Smith
Charitable Trust Distinguished Professor in Cancer
Research — to conceptualize and optimize a unique gene
assembly process to create highly consistent and effective NeoAg
building blocks driving effector T cells consistently in
vivo.
As a model for designing human NeoAg vaccine cassettes, the
scientists first sequenced mouse tumor DNA and RNA and used defined
AI-based approaches to identify the collection of “mistakes” that
were most immune activating in any particular tumor. Assembly and
clipping of each specific tumor mistake were assembled into a
sequence of immune strings that used DNA intervening sequences to
physically “separate” each individual NeoAg in the string. Next,
the string’s ability to drive was evaluated to ensure that the
placement of a particular neoantigen along the string was capable
of retaining its immune potency. They documented that the final
cassette strings as DNA vaccines induced potent induction of T cell
immunity and could regress and clear tumors in preclinical model
studies. Without the NeoAg vaccination, the control models’ immune
systems ignored tumors when challenged which grew unabated in these
animals. They then studied sequences derived from human tumors as
well to further advance this research towards the clinic.
While neoantigens produced by liver cancer don’t typically
trigger strong immune responses, the team hypothesized that their
improved neoantigen vaccine strings as well as the inclusion of
immune-stimulating signals that the lab had developed could train
the immune system to better recognize and eradicate the
malignancy.
Accomplishments in the lab validated the utility of assembling
specifically designed larger collections of NeoAgs in a single
vaccine (40Ags), including specific processing signals to preserve
the integrity of each potential NeoAg in the string. The team’s
technology was also able to include specific T cell expansion
signals associated with activation of CD4 and CD8 Killer T cell
immunity built into the vaccines’ DNA designs, among other
innovations; these design elements showed that the technologies
were well tolerated and could protect preclinical models from
cancer challenge.
“We’re very pleased to have played a role, working together with
Geneos and the entire team in advancing this important, exciting
technology and to see its impact in patients in the important GT30
clinical trial,” said David B. Weiner, Ph.D.
“Advancing the next generation of nucleic acid immune weapons for
impacting intractable cancers is a major focus of our team.”
ABOUT THE WISTAR INSTITUTEThe Wistar Institute
is the nation’s first independent nonprofit institution devoted
exclusively to foundational biomedical research and training. Since
1972, the Institute has held National Cancer Institute
(NCI)-designated Cancer Center status. Through a culture and
commitment to biomedical collaboration and innovation, Wistar
science leads to breakthrough early-stage discoveries and life
science sector start-ups. Wistar scientists are dedicated to
solving some of the world’s most challenging problems in the field
of cancer and immunology, advancing human health through
early-stage discovery and training the next generation of
biomedical researchers. wistar.org