My third day at the AACR Annual meeting was a day of phenomenal presentations. I am struggling to choose just one to tell you about because I attended multiple inspiring, thought-provoking, and even entertaining talks today. I decided to report on the plenary presentation by Steven A. Rosenberg entitled “T-cell therapy targeting unique cancer mutations” because I think this story has the most potential to positively impact patient outcomes.
Dr. Rosenberg started his presentation by saying that solid epithelial cancers often don’t respond well to therapy. His team’s approach has been to use adoptive immunotherapy, which utilizes TILs (tumor-infiltrating lymphocytes) grown in vitro and then transferred back to the patient. The advantage of this method is that you can select with high affinity to cancer antigens and activate the T cells prior to transferring back to the patient. Additionally, you can manipulate the patient host prior to re-infusion by chemotherapy or lymphodepletion. Approximately 55% of patients achieve a durable response to this therapy.
Now Dr. Rosenberg’s research has focused on what the TILs actually recognize that enable the destruction of the tumor cells. To activate the TILs, Dr. Rosenberg explained that cancer antigens must be processed into an approximately 9-11 amino acid peptide that fits into the groove of an MHC molecule. So, only a very few cancer mutations will be immunogenic. His lab has surveyed the mutations present in a particular patient, then made all possible combinations of peptides with the mutation. Minigenes encoding these peptides are transfected into antigen-presenting cells (APCs), which are then co-cultured with the patient’s own T cells. They test to see if any of the peptides presented on the surface of the APCs can be recognized by the T cells. Dr. Rosenberg stressed that there was no prediction involved in this work; models generally don’t accurately predict tumor antigens. In this approach, each mutation is empirically tested.
The immunogenic mutations identified seemed to be unique to each patient. For example, when they looked at gastrointestinal cancers, they examined mutations from 72 patients and identified 120 immunogenic peptides; only one of which was shared among two patients – none of the mutations identified as immunogenic were driver mutations. This work led the Rosenberg group to pose two hypotheses: first, it is the recognition of random somatic mutations that is the final common pathway explaining cancer regression from immunotherapy, and second, any intracellular protein can potentially be a cancer antigen.
There is good news and bad news that comes out of these hypotheses: the good news is virtually all cancers have mutations that can be neoantigens; the bad news is the process to identify these neoantigens must be highly customized for each patient. Ongoing work is attempting to make the process less customized and therefore less labor intensive, so that the therapy can be offered to a greater number of patients. He noted that there are many mutations in driver oncogenes that can be shared among patients. For example, 51% of pancreatic cancer patients have a mutation at glycine 12 of KRAS. Making a KRAS G12 peptide library and preparing APCs for screening could be beneficial to a large portion of pancreatic cancer patients. P53 is a tumor suppressor gene that is also frequently mutated, and the mutations cluster in a limited number of “hotspots” in the gene. Preparing a peptide library for these hotspot regions of the protein could also potentially be a tool applicable for many patients.
The selected T cells that are re-infused into the patient can expand 1,000-fold in the days after transfer and persist at low levels indefinitely. Visuals from clinical cases are always very impactful for me, and Dr. Rosenberg showed several images of patients with bodies racked with metastatic lesions that were completely resolved after the adoptive T cell therapy. It was truly awe-inspiring to see how this innovative method was able to completely turn around the prognosis for the sickest patients and restore them to health. I am very hopeful that current work in the Rosenberg lab, and other labs, will continue to refine and make this therapy more widely available.
Don’t miss out on the latest data we presented at AACR on reference standards for TMB, liquid biopsy, NTRK, fusion RNA, and more in the poster sessions. You can download our posters here.