Checkpoint inhibitors, such as nivolumab and ipilimumab, approved by
the FDA for use against lung cancer, metastatic melanoma, head and neck
cancer, and Hodgkin lymphoma, help the immune system recognize cancer
cells by revealing evidence of mutated proteins called neoantigens on
the surface of cancer cells.
Results of an initial study of tumors from patients with lung cancer
or head and neck cancer suggest that the widespread acquired resistance
to checkpoint inhibitors may be due to the
elimination of certain genetic mutations needed to enable the immune
system to recognize and attack malignant cells.
‘The widespread acquired resistance to checkpoint inhibitors may be due to the elimination of certain genetic mutations needed to enable the immune system to recognize and attack malignant cells.’
The study, conducted by
researchers on the cells of five of their patients treated at the Johns
Hopkins Kimmel Cancer Center, is described online in Cancer Discovery
"Checkpoint inhibitors are one of the most exciting recent advances
for cancers, but the mechanism by which most patients become resistant
to these therapies has been a mystery," says Victor E. Velculescu, program leader in the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
and professor of oncology. Clinical trials with the drugs to date have
shown that nearly half of patients with lung cancers eventually develop
resistance to this class of drugs for reasons that have been unclear.
To investigate why checkpoint inhibitors so often stop working, Velculescu; Valsamo Anagnostou, instructor of oncology at the Johns Hopkins University School of
Medicine; Kellie N. Smith, a cancer immunology research associate
at the Johns Hopkins University School of Medicine; and their
colleagues at the Bloomberg~Kimmel Institute for Cancer Immunotherapy
studied tumors of four patients with non-small cell lung cancer and one
patient with head and neck cancer who developed resistance to two
different checkpoint inhibitors: a drug called nivolumab that uses an
antibody called anti-PD-1, or nivolumab used alone or in combination
with a second drug called ipilimumab, which uses an antibody called
Using biopsies of the patients' tumors collected before the start of
treatment and at the time patients developed resistance, the
researchers performed large-scale genomic analyses to search for
mutations specific to the cancer cells in all of each patient's 20,000
The scientists' genomic search narrowed in on genes that code for
the production of antigens, which serve as a source of identification to
the immune system. Cancer cells may contain mutations in genes that
code for antigens, producing misshapen or otherwise altered antigens
that are known to scientists as neoantigens. Such neoantigens are
foreign to the immune system, and thus, the cancer cell is flagged for
destruction, usually with the help of immunotherapy drugs.
The scientists found that after the patients developed resistance to
immunotherapy, all of their tumors had shed between seven and 18
mutations in neoantigen-coding genes. By getting rid of those mutations,
the tumor cells' neoantigens look less foreign to the immune system and
may go unrecognized, say the scientists.
The researchers found that the tumors had lost these mutations by
various means, including immune-mediated elimination of cancer cells
containing these mutations, leaving behind cancer cells without the
mutations, or by deleting large regions of their chromosomes in all
"In some instances," says Anagnostou, "we found that chromosomes in
the cancer cells' nuclei were missing an entire arm containing these
To confirm that the missing mutations were important for generating
an immune response, the researchers cultured a subset of the neoantigen
protein fragments containing the tumor mutations with immune cells taken
from three patients' blood samples. Between one and six of the
eliminated neoantigens were shown to generate a specific immune cell
response in each of the patients.
"Our findings offer evidence about how cancer cells evolve during
immunotherapy," Velculescu says. "When the cancer cells shed these
mutations, they discard the evidence that would normally lead them to be
recognized by the body's protective immune cells."
Velculescu, Anagnostou, Smith and their colleagues say they plan to
determine how broadly this phenomenon occurs in other cancer types and
potentially use it to develop new ways to improve current cancer
immunotherapies. For example, they say, the mutated neoantigens present
in tumor cells before therapy could give clues as to which patients'
tumors might develop resistance. The findings could also advance the
development of new checkpoint inhibitors less likely to trigger
resistance or personalized immunotherapy approaches.
Four checkpoint inhibitors are currently approved by the FDA
- nivolumab, pembrolizumab, atezolizumab and ipilimumab - to treat
melanoma, lymphoma, bladder, lung and head and neck cancers. The drugs
cost more than $10,000 per month, an expense that has fueled efforts to
improve their value and patient selection.