Cancer-free after immunotherapy treatment: Treating advanced colon cancer – targeting KRAS gene mutation by tumor-infiltrating lymphocytes (TILs) and Killer T-cells (NK)
Reporter: Aviva Lev-Ari, PhD, RN
By DENISE GRADY DEC. 7, 2016
The research involves cancer-fighting immune cells called tumor-infiltrating lymphocytes, or TILs. These are white blood cells that swarm around tumors, a sign that the immune system is trying to attack the cancer. Dr. Rosenberg has been studying TILs for decades, with the goal of enhancing their ability to fight the disease and using them as a treatment.
An attempt to treat another patient with tumors much like Ms. Ryan’s did not work, almost certainly because the researchers could not produce enough highly targeted TILs, Dr. Rosenberg said.
So far, the cells have worked best against advanced melanoma, a deadly form of skin cancer. By extracting TILs from tumors, multiplying them in the lab and then returning them to the patient, Dr. Rosenberg’s team has produced long remissions in 20 to 25 percent of patients with that disease.
In March 2015, she got in. Whether the screen shots were a deciding factor is not clear. Dr. Rosenberg said the team had been watching her progress and brought her in as soon as they identified operable tumors.
A month later, the researchers performed surgery, removing several lung tumors to search for TILs.
Ms. Ryan’s tissue turned out to be a medical gold mine. She had a KRAS mutation and her TILs included killer T-cells that locked onto the mutation like guided missiles.
Her T-cells were able to recognize the mutation because she has an uncommon tissue type, which is a genetically determined trait. As a result, she carries a certain protein on the surface of her cells that plays an essential role in displaying the KRAS mutation so that cancer-killing cells can find it and attack.
Best of all, from a scientific standpoint, was that Ms. Ryan’s KRAS mutation is shared by many other patients with colon and pancreatic cancers. Those who share her tissue type may also be good candidates for treatment with TILs.
Researchers say they now have a blueprint that may enable them to develop cell treatments for other patients as well. The killer T-cells have surface molecules called receptors that lock onto mutated cells, and it may be possible to genetically engineer patients’ T-cells to give them those receptors and their cancer-targeting ability.
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer
Eric Tran, Ph.D., Paul F. Robbins, Ph.D., Yong-Chen Lu, Ph.D., Todd D. Prickett, Ph.D., Jared J. Gartner, M.Sc., Li Jia, M.Sc., Anna Pasetto, Ph.D., Zhili Zheng, Ph.D., Satyajit Ray, Ph.D., Eric M. Groh, M.D., Isaac R. Kriley, M.D., and Steven A. Rosenberg, M.D., Ph.D.
N Engl J Med 2016; 375:2255-2262 December 8, 2016 DOI: 10.1056/NEJMoa1609279
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02–restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.
12/07/2016 04:00 PM EST
Researchers identified a method for targeting the cancer-causing protein produced by a mutant form of the KRAS gene.
This article has no abstract; the first 100 words appear below.
Metastatic gastrointestinal cancers that express products of mutant KRAS genes have one of the most dismal outcomes of all solid tumors and present an unsolved problem in cancer medicine. An activating point mutation in one of genes encoding Ras was the first somatic point mutation identified in a human cancer, and its discovery established the role of somatic mutations as the common driver of oncogenesis.1,2 The presence of a T-cell immune infiltrate in surgical specimens at the time of diagnosis is more prognostic of survival than anatomic Dukes staging,3 which suggests that natural immune surveillance can have a powerful . . .