Doctors in Portland Oregon successfully used T cells to fight pancreatic cancer cells in one patient. Now they want to see how often and how long their treatment works
T lymphocytes are capable of destroying cancerous cells, but they have trouble recognizing them. B lymphocytes are experts in identifying and marking targets, but they have no killer mechanism.
During the last few decades a researcher in Israel learned how
to plant a gene into the cytoplasm of a T cell, and the gene gave the cell the ability
both to recognize and destroy worrisome proteins. At the NIH a researcher named Steve Rosenberg
removed T cells from a person with lymphoma.
His team added a gene
to the T cells and the gene allowed the cells to recognize CD 19. That’s an antigen
that is only found on the surface of the healthy and malignant B cells. After the
gene was added, the researchers allowed the changed T cells to multiply. Then they
poured them back into the person’s bloodstream and the patient became
and remained cancer free.
Researchers at Providence hospital in Oregon used a similar
approach when they successfully treated a person with pancreatic cancer.
They used tumor infiltrating lymphocytes that recognized a mutant protein on the surface of pancreatic cancer cells.
The
protein (for historical reasons) is called KRAS.
In healthy cells, the KRAS protein supports normal cell growth and proliferation but it sometimes mutates. Certain of its malformed proteins can cause uncontrolled cell growth and cancer.
Using what they called “gene-engineered adoptive cell therapy” the researchers ran the blood of a person with pancreatic ductal adenocarcinoma through a machine that strained out the T cells. Then they returned the blood to the patient.
Then they engineered the T cells so the T-cell receptors (TCRs) could target “hot-spot” mutations commonly
found in pancreatic cancer. They “transduced” two of the T-cell
receptors (TCRs) so they would target the mutant KRAS molecule G12D expressed
by the cancer cells. The KRAS mutation occurs in 33 percent of tumors with KRAS mutations.
The T-cells were amplified in magnitude and potency, and returned to the patient
through intravenous infusion. During the six months that followed the infusion the cancer shrank and the patient felt well. One patient. One success. Now the doctors are enrolling people in a
study they want to find out how often
and how long the treatment works.
The following is taken from their official letter the researchers send to interested physicians:
JUNE
7, 2022 EARLE A. CHILES RESEARCH INSTITUTE
Earle A.
Chiles Research Institute is among a handful of centers in the
world capable of developing and administering adoptive
cell therapy, a highly personalized type of immunotherapy. We are
recruiting adult patients with certain solid cancers for a phase I clinical
trial to evaluate the safety and effectiveness of gene-engineered, adoptively
transferred T cells.
T
cells are a type of immune cell which, under the right circumstances, can
recognize and attack cancer cells. T-cell
transfer therapy is a form of adoptive cell therapy that
enhances T cells in a laboratory so they can find and destroy cancer cells more
effectively. While T-cell transfer therapy has been successful in treating some
blood cancers, many solid cancers do not respond and continue to
grow.
Our
researchers are studying whether T-cell transfer therapy and genetic
engineering can shrink solid cancers that are resistant to therapy. In their
landmark New England Journal of Medicine article Neoantigen T-Cell Receptor Gene
Therapy in Pancreatic Cancer, Rom Leidner, M.D., Eric Tran, Ph.D.,
and Providence colleagues provide the world’s first report of metastatic
pancreatic cancer regression through T-cell transfer therapy with
genetically-engineered T cells.
Drs.
Tran and Leidner have opened a phase 1 clinical trial to evaluate this therapy
in a small group of patients with solid cancers that are unresponsive to
standard care.
Targeting KRAS hotspot
for incurable epithelial cancers
Epithelial
cancers are carcinomas that
originate in the epithelial tissue found in the skin and organs throughout the
body. They account for a broad array of the most common solid cancers –
including breast, colon and lung – and are responsible for 85% of annual cancer
deaths.
In
this study known as Hotspot TCR-T, T cells from patients are genetically
engineered to express a T-cell receptor (TCR) that redirects the T cells to
target a common cancer mutation called a hotspot. One such hotspot is a mutated
form of the KRAS
oncogene.
In
healthy cells, the KRAS protein supports normal cell growth and proliferation.
Mutated KRAS variants result in uncontrolled cell growth and are present in 30%
of epithelial cancers.
Triple combination
therapy
To
develop this therapy, T cells are obtained from a patient’s blood. In our Adoptive
Cell Therapy Lab, the T cells undergo TCR gene-engineering to target
hotspot mutations expressed by the patient’s cancer. Then they are amplified in
magnitude and potency, and returned to the patient through intravenous infusion.
This therapy is experimental.
Patients
enrolled in the study will also receive two additional immunotherapy agents
that may enhance the activity and effectiveness of the transferred T
cells: pembrolizumab and CDX-1140.
This
investigator-initiated study is led by Rom Leidner, M.D., medical director,
Providence Head and Neck Cancer Program, and Eric Tran, Ph.D., assistant member
and leader of the Adoptive Cell Therapy Lab at the Earle A. Chiles Research
Institute, a division of Providence
Cancer Institute of Oregon.
Providence
Portland Medical Center in Portland, Oregon, is the only location to offer the
study.
Get
the full details here:
Eligibility
Up
to 24 patients from the United States* will be enrolled to the study. Patients
with metastatic or locoregionally advanced epithelial cancers which are
considered incurable (have failed prior treatments or are not candidates for
surgery) may be eligible.
These
include certain cancers of the breast, gastrointestinal tract (colon, stomach,
gallbladder, bile ducts, pancreas and liver), lung, prostate and bladder.
Patients with melanoma or cancers of the blood, soft tissue (sarcomas) or
neurological tissue are not eligible.
To
qualify, participants must meet several eligibility criteria,
including the following KRAS mutations and human leukocyte antigen (HLA)
typing:
·
KRAS G12V with HLA-A*11:01 or HLA-DRB1*07:01
·
KRAS G12D with HLA-A*11:01 or HLA-C*08:02
Patients
should contact their oncologist to inquire about their KRAS and HLA statuses.
To help determine patient eligibility, oncologists can coordinate two required,
pre-screening tests:
1. Tumor next-generation
sequencing (NGS) – KRAS G12D or KRAS G12V mutation *
2. HLA typing – High
Resolution: A, B, C, DRB1, DQB1, DPB1
One
lab that offers HLA typing is Kashi
Clinical Laboratories. It offers both physician ordering and direct
patient ordering. Because the study requires "high resolution"
HLA typing, orders must be made by calling: (877) 879-1815 and
requesting the “High Resolution Combination: A, B, C, DRB1, DQB1,
DPB1".
The
cost of these tests is not covered by the Hotspot TCR-T research study and will
be the responsibility of the patient or their insurance.
*Participation
in this study is limited to patients from the United States. The study is not
accepting international patients at this time.
Oncology referral
information
To
refer patients whose NGS testing and HLA typing match the requirements listed
above, oncologists can contact our team by phone or email:
·
Call 503-215-1979
·
Send an email to CanRsrchStudies@providence.org
^ NGS is a technique for determine the sequence of DNA or RNA or the entire human genome. Each of the three billion bases in the human genome is sequenced multiple times. then the sequences are analyzed. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841808/
https://www.nejm.org/doi/full/10.1056/NEJMoa2119662
ADDENDUM:
There’s a new small molecule that prolongs the life of
a few people with pancreatic cancer. It
targets a protein on the surface of cancer cells. The protein has mutated, has become an
oncogene—a gene that compels cancer cells to reproduce rapidly and to live a
long life. Mutations in the protein—the “Kirsten rat sarcoma viral
oncogene homologue (KRAS) gene”--are found in
approximately 90% of pancreatic ductal adenocarcinomas, which is the most
prevalent histologic type of pancreatic cancer. KRAS G12C, however, only occurs 1-2 percent of the time.
The mutated KRAS protein was considered to be “undruggable” for many years, owing mainly to its complex biochemical characteristics and limited number of binding sites. Analysis of the crystal structure of the KRAS G12C bound to guanosine diphosphate (GDP) (by Ambien scientists) revealed a previously unknown pocket beneath the switch II region that allowed for direct targeting of the mutated protein.
Sotorasib is a small molecule that irreversibly and selectively binds to this pocket. It locks it in the inactive state and inhibits oncogenic signaling. “
Now available in Europe, Sotorasib is the first approved targeted therapy for tumors with a KRAS mutation. The following is a new study of the drug in patients with advanced pancreatic cancer:
KRAS p.G12C–Mutated Advanced Pancreatic Cancer New England Journal of Medicine 12/21/2022
Here, we report the results in heavily pretreated patients with KRAS p.G12C–mutated pancreatic cancer. Eight patients had a confirmed objective response. The median progression-free survival was 4.0 months, and the median overall survival was 6.9 months. https://www.nejm.org/doi/full/10.1056/NEJMoa2208470?query=featured_home
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