THE IMMUNE SYSTEM AND CANCER
To
an observer from outer space the human body might look like an assemblage of 30,000,000,000,000
cells, tiny structures that have a variety of forms and functions.
One type of cell, the
killer T lymphocyte is a defender. It kills
cancer cells and destroys bacteria and viruses that enter our bodies through
wounds or breeches in our skin and mucosal barriers. It also constrains the slew of microorganisms
that live in our bodies.
HIV is a virus that
attacks, occupies, and destroys T cells.
After the invading virus has substantially reduced the number of body-defenders,
a number of organisms “wake up”, reproduce and cause illness and death.
When a cell divides, 3 billion pairs of nucleotides separate and become positive and negative individual strands. Each strand is complementary to the other strand. After they part each strand combines with a 3 billion new nucleotides. The process is quite efficient. Mistakes in the nucleotide sequence (mutations) are uncommon and usually harmless. There are 20,000 genes and they comprise about one percent of the DNA. When a nucleotide that is part of a gene is misplaced serious mutations can occur and create problems.
Cancers are collections of cells that multiply rapidly, don’t die, and spread through the body. We think they start in a cell whose genes have accumulated a number of significant mutations over many years. Sometimes a cell becomes cancerous because a special “driver” gene mutates. At other times the cell is at the tipping point –and when it acquires an additional mutation it becomes a cancer cell.
Peter Campbell’s group at the Wellcome Trust Sanger Institute.” analyzed mutations in over 7600 tumors from 29 different types of cancers. They found around 99 percent of all coding mutations found in cancer cells were actually harmless and can be tolerated by the cell without affecting its survival, but a few specific mutations could drive cancer. They estimated that between one and 10 mutations in genes are required for a healthy cell to turn cancerous. About four mutations per patient on average drive liver cancers, whereas colorectal cancers typically require 10 or so driver mutations.'”
When malignant cells are bizarre enough, T cells (sometimes??) recognize them as intruders and they try to destroy them.
James Allison was the
researcher who observed T cells that attached to malignant cells and injected a
poison. The cancer cells survived because they produced an antidote. Allison and
his people developed an antibody that blocked the antidote, and that allowed the
poison to destroy the cancer. Antidotes similar to the ones Allison’s
associates developed are the immunotherapy drugs of today. For his work Allison was awarded a Nobel
Prize.
Zelig Eshar and Steve Rosenberg each,
independently and separately, developed a technique for programming T
lymphocytes so they can identify certain cancers. Their process starts by filtering a person’s
blood. T cells are collected and the
rest of the blood is returned to the body. In the lab a gene called
chimeric antigen receptor or CAR is inserted into the T cell. The CAR targets a protein on the surface of
certain cancer cells. Then large numbers of altered T cells are grown.
Antibodies normally have two arms that
fasten onto the same invader. A company in Germany created an antibody each
of whose 2 arms targeted a different protein.
The medication they developed connects T cells to lymphoma cells. For details see blog titled A STEP IN THE WAR
AGAINST CANCER
In
2021 the FDA approved Teclistamab a “medication” that binds to two proteins-- one
of them is only found on the surface of T lymphocytes. The other is only present on the membrane of malignant
myeloma cells. When it was given to 165 patients with refractory myeloma, 63.0% got
better and 39.4% had a complete response that lasted (median duration) 18.4
months. It is
being marketed by Janssen, a division of Johnson and Johnson.
https://www.nejm.org/doi/full/10.1056/NEJMoa2203478
Another
immunotherapy approach has worked on one person and we are hopeful. It involves mutant KRAS proteins on the
surface of certain cancers. Much as weather
vanes once dotted rooftops, the outer surfaces of many normal cells are covered
with genetically created proteins called KRAS.
They help cells analyze the goings on elsewhere in the body, and the information
they provide influences the growth and death of the cell. Certain mutations of
the gene, and the protein it makes are thought to cause cancers to grow
wildly. Recently researchers in Portland Oregon obtained mutated KRAS genes
and injected them into a specialized virus.
Then they used the virus to insert the mutated genes into T cells and taught
the T cell receptor to recognize mutated KRAS
genes on the surface of cells. The
researchers grew a large number of modified T lymphocytes in their lab, and
they infused them into a patient with wide spread pancreatic cancer. Over the subsequent months the cancer in the
person who got the infusion grew smaller and smaller. The approach is currently
restricted to people who have certain HLA proteins on the surface of their
cells.
On May 10 2023 the
Sloan Kettering researchers published a study of 16 people who had a surgical
resection of their pancreatic cancers and were then vaccinated with an individualized mRNA vaccine in an attempt to
activate their T cells and prevent recurrences.
It seems to be working. SEE
BLOG: .An experimental vaccine delayed the recurrence of pancreatic cancer
“One swallow
does not a summer make”, but the approach gives us hope.
https://www.nejm.org/doi/full/10.1056/NEJMoa2201445?query=featured_home
https://www.nejm.org/doi/full/10.1056/NEJMoa2119662?query=featured_home
https://www.britannica.com/science/cell-biology
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518513/
Another
immunologic approach to malignant plasma cells employs a lab created antibody
called Teclistamab. The “medication” binds
to two proteins-- one of them is only found on the surface of T lymphocytes. The other is only present on the membrane of malignant
myeloma cells. The drug is injected
subcutaneously weekly into a person who has widespread multiple myeloma (a
cancer of the plasma cells). It binds to
both surface proteins and it connects the myeloma and T cells. After they are hooked together, the T cells
destroy the myeloma cells.
There’s another immunotherapy approach that has worked on
one person and we are hopeful. It
involves mutant KRAS proteins on the surface of certain cancers. Much as weather vanes once dotted rooftops,
the outer surfaces of many normal cells are covered with genetically created
proteins called KRAS. They help cells
analyze the goings on elsewhere in the body.
The information they provide influences the growth and death of a cell. Certain
mutations of the gene and the protein it makes are thought to cause cancers to
grow wildly.
“About 95% of
pancreatic cancer tumors have a mutant
KRAS gene on their surface. “RAS” genes
are oncogenes – genes that, when altered, can transform healthy cells into
cancer cells.” (According to pancreatic cancer.org,)
Mutated KRAS proteins were first found on the
surface of a Kirsten rat sarcoma 40 years ago. Over the last 40 years scientists have sought a drug or
treatment that will affect mutated KRAS genes without harming normal KRAS.
Recently researchers in Portland Oregon obtained mutated KRAS genes and injected them into a specialized virus. Then they used the virus to insert the mutated genes into T cells. We don't know how, but the researchers programmed/taught the T receptor to recognize and attach themselves to mutated KRAS proteins on the surface of the cancer cells.
"T-cell receptors bind to certain antigens (proteins) found on abnormal cells, cancer cells, cells from other organisms, and cells infected with a virus or another microorganism.” (NCI)
The researchers then grew a large number of modified T lymphocytes in their lab, and they infused them into a patient with wide spread pancreatic cancer.
In the body, presumably, the T-cells became attached to the mutated protein and the affixed T cells destroyed the cancerous cells.
Over the subsequent
months the cancer in the person who got the infusion grew smaller and smaller.
The approach is currently restricted to people who were born with certain HLA proteins on
the surface of their cells. (A group of
researchers in Belgium are trying to develop a process that Overcomes HLA restriction in clinical
trials.)
“One swallow
does not a summer make”, but the approach gives us hope.
https://www.nejm.org/doi/full/10.1056/NEJMoa2201445?query=featured_home
https://www.nejm.org/doi/full/10.1056/NEJMoa2119662?query=featured_home
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