January 2015, Vol. 2, No. 1
Immune Checkpoint Blockades: The Future of Cancer Therapy
Using the body’s own defenses to kill cancer may sound like the realm of science fiction. However, in the keynote lecture presented at the 2015 Gastrointestinal Cancers Symposium, T cells and antibodies were shown adept at recognizing and targeting antigens created by tumor mutations as they evolve within patients.
“The immune system has the capacity to keep up with the changing somatic mutations that are occurring with cancer,” said Ronald Levy, MD, professor at Stanford University and chief of the division of oncology in the Department of Medicine, “so it’s only a matter of figuring out how to attune this immune system to do its job better….It’s fighting fire with fire.”
Identifying Targets for the Immune System
Despite the improvements in cost and technology for high-throughput sequencing of DNA, Levy has viewed the enterprise as misguided – until now. “Sequencing has been largely directed toward trying to find actionable mutations and drugs that target these actionable mutations,” he related, “when, instead, the value may turn out to be identifying targets for the immune system.”
According to Levy, mutations in DNA have the capacity to be seen by the immune system because they create proteins with point mutations in them that turn into peptides and are presented on the surface of the tumor cell.
“The T cells can see these peptides, these mutated sequences coded for by the mutations in the DNA,” he said. “It’s just a matter of figuring out how to get these T cells that are around to attack the cancers.”
Surprisingly, the barriers to successful immunotherapy, as Levy sees them, have less to do with the T cells themselves than the tumors that suppress them. “It’s emerged recently that the tumor cells have signals that tell the T cells not to kill them,” he said, “so-called ‘don’t kill me’ signals that turn down the T cells in the environment recognizing the antigens.”
These Signals Can Be Inhibited
As reported by Levy, the PD-1 ligand 1 is one of the signals on the tumor cells that tells T cells, through a counterreceptor on the tumor cell called PD-1, to turn down the activity.
“T cells in the environment secrete factors, including gamma interferon, that dial up the PD-1 ligand on the tumor cell,” he explained, “so this is an adaption by the tumor cell to the incoming T cell, which has the capability of recognizing the antigens that are on the tumor.”
According to Levy, the goal for the immunology community is to interrupt this negative signal – “take the brakes off the T cells” – and let the T cell do its job.
One of the early successes of immune checkpoint blockade, cited by Levy, was a phase 1 trial in Hodgkin disease presented at the 2014 ASH meeting in Orlando, FL. After all conventional therapies, including bone marrow treatment, had failed, all the patients responded to the PD-1 blockade by the PD-1 antibody – especially remarkable given the dynamics of the disease.
“It’s really incredible,” said Levy, “because in Hodgkin we have the amplification of the gene for PD-1 ligand in a significant fraction of patients that results in the dialing up of the expression of PD-1 ligand by the tumor cells….There’s no doubt this is going to be the poster child for PD-1 blockade in all of cancer because of the dialing up of the target in the Reed-Sternberg cell.”
Levy also stressed that treatment success was not limited to a single type of cancer. A recent study of the response of metastatic melanoma showed a significant fraction of patients responding dramatically to the blockade.
“We have evidence of amazing activity in a variety of cancers simply by taking the brakes of this 1 signal – PD-1 ligand – with a variety of candidate antibodies,” Levy said. “This is quite remarkable in our history of cancer treatment.”
What Questions Remain?
In spite of the progress, many questions remain. “Why do some tumors respond and not others?” asked Levy. “We have lymphoma responding but not myeloma. We have gastric responding but not colon….And how do we increase these response rates? We’re talking 90% response rate in Hodgkin lymphoma but only 30% to 40% in melanoma and 20% response rate in lung cancer. So how do we get the response from 20% up to 80%?”
One idea for increasing this rate is combination therapy to enhance each treatment’s respective activity. In an example provided by Levy, colon cancer was cured in a majority of mice by a combination of a tyrosine kinase inhibitor and a PD-1–blocking antibody. “When we put these 2 together,” said Levy, “we get amazing effects….This looks like the future to me.”
According to Levy, trials combining tyrosine kinase inhibitors with immune checkpoint–blocking antibodies are already set to begin this year.
“I think that we’ll be able to make PD-1 blockade work better by combining positive and negative signals and adding tyrosine kinase inhibitors to these immune therapies. And who knows?” concluded Levy, “Maybe one day we’ll be treating cancer without cytotoxic chemotherapy.”
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