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Targeting mutations a 'complex' must in cell therapy for solid tumors
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PHILADELPHIA — Effectively treating solid epithelial cancers will require targeting a patient’s somatic cancer mutations, leading to highly complex, individualized treatments, according to Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI.
Rosenberg provided his blueprint for cancer immunotherapy directed against common epithelial cancers during last week’s CAR-T and the Rise of the Cellicon Valley event at the University of Pennsylvania. The blueprint included targeting the immunogenic somatic mutations unique to each patient’s cancer and raising a library of T-cell receptors against shared cancer mutations.
“Cell transfer therapy can lead to durable regressions with metastatic cancers that are refractory to other treatments,” Rosenberg told the audience. “T cells that recognize unique somatic mutations can be found in patients with common epithelial cancers, and the identification and targeting of mutations of each cancer — or shared mutations — has the potential to extend cell therapy to patients with these common tumors.”
Rosenberg said the major challenge facing modern cancer immunotherapy is “the development of effective immunotherapies for patients with metastatic epithelial solid cancers that cannot be cured by any available treatment and result in over 90% of cancer deaths.”
There is a large unmet need for therapies that treat solid epithelial cancers, he said. Current immunotherapies, including checkpoint inhibitors, have low response rates — usually in the single digits — for most epithelial cancers, despite achieving some success for treating melanoma, renal cancer and some types of bladder and lung cancer.
Cancers that occur in organs with ducts, such as the colon, stomach, prostate, and ovaries, are responsible for most cancer deaths, per Rosenberg.
“It’s the epithelial linings of the ducts that are constantly turning over and as they turn over, they make mistakes in DNA replication and its these mutations that actually result in the cancer,” he said.
Rosenberg acknowledged the increasing volume of research being done on expanding chimeric androgen receptor T-cell therapy to the treatment of solid epithelial cancers. His lab has conducted three different trials using CAR T cells for solid tumors that have shown no clinical benefits.
Fifty-six patients have received treatment in these trials at the NCI, and none have responded to treatment.
“CAR T cells require the use of monoclonal antibodies that recognize molecules on the cell surface, and that’s a challenge for the application of CAR T cells in solid cancers,” Rosenberg said. “No one has yet found an antibody that is unique for cancer cells and not also present on normal cells, and some of the best minds in the field have tried to develop these monoclonal antibodies.”
He said that if a cell therapy is administered and it recognizes an antigen on a normal cell, these cells are still highly sensitive to destruction and will be killed as quickly as a cancer cell. Additionally, Rosenberg noted most monoclonal antibodies in use today target growth factor receptors on the surface of cells, which means they do not kill cancer cells but instead decrease their ability to grow.
T Cell Receptors vs. CARs
NCI is working on the use of conventional T cell receptors for the treatment of solid epithelial cancers. So far, Rosenberg’s lab has had an approximate 15% response rate to T-cell receptor treatments that target somatic mutations in epithelial cancers.
“By targeting multiple mutations, we can overcome the heterogeneity that exists as cancers grow and metastasize. ... One of the unique aspects of this treatment is that it’s not unique to a cancer type — it’s attacking mutations,” he said. “And because all cancers have mutations, we have seen responses across a variety of cancers.”
Rosenberg said it currently takes his lab about 6 to 8 weeks to manufacture a personalized T-cell treatment for patients.
“We are working hard now on trying to automate this process with robots so that we can generate treatments for multiple patients at once.”
The ability to treat multiple solid epithelial cancers is a positive development in a field that has seen very few changes in available therapies to treat metastatic cancer over the past half century, Rosenberg asserted.
“The good news is that virtually all cancer patients will be potentially eligible [for T Cell receptor therapy] because mutations are what’s causing the cancer,” he said.
“The bad news is that treatments will have to be unusually highly personalized, and thus are likely to be complex in their application. Because patients do not share antigens, we are going to have to develop an individual drug for every patient if we are going to have impact on the treatment of cancer.” – by Drew Amorosi
Disclosure : Rosenberg reports receiving research support through his institution from Kite Pharma and Iovance Biotherapeutics.