NEW YORK – Gritstone Bio is betting that an autologous T-cell therapy synergistically combined with its cancer vaccine may be particularly efficacious for the fraction of patients with KRAS-mutated solid tumors who also carry a specific HLA allele.
Checkpoint inhibitors have been very successful in inducing immune responses against solid tumors, but only a minority of patients experience sustained benefit from them. For most, the responses are variable and fleeting. According to Andrew Allen, founder and CEO of Gritstone Bio, that's because solid tumors are able to successfully hide from the immune system. His company has taken on the challenge of improving T-cell responses against solid tumors by developing individualized and off-the-shelf neoantigen immunotherapies in combination with checkpoint inhibitors.
In its latest effort, Gritstone has teamed up with the National Cancer Institute to explore the activity of its off-the-shelf KRAS-directed vaccine candidate, SLATE-KRAS, with an autologous T-cell therapy expressing a T-cell receptor targeting mutated KRAS. Steven Rosenberg, chief of the surgery branch at NCI's Center for Cancer Research, developed the T-cell receptor therapy that will be paired with Gritstone's vaccine, and he will also lead the Phase I trial, in which the combination will be studied. Investigators will recruit patients with metastatic cancer whose tumors carry a KRAS G12V or G12D mutation to receive the SLATE-KRAS vaccine as well as the KRAS-targeted TCR T-cell therapy.
Cell-based therapies, such as CAR T-cell, tumor infiltrating lymphocytes, and TCR T-cell therapies like the one developed by Rosenberg, have yet to come to market in solid tumor settings. However, CAR T-cell treatments are marketed for B-cell hematologic malignancies because a range of targetable markers in blood cancer cells, such as CD19, CD20, and BCMA are available, and the patient can survive the loss of normal B cells.
"We don't have that luxury in solid tumors," Allen said. For example, he pointed out that every lung cancer or colon cancer has EGFR. "Of course, EGFR is found on normal tissues, as well. The problem is you get rampant toxicity. For these reasons, CAR T in solid tumors has struggled to really have the same kind of efficacy that we've observed within B-cell malignancies."
The workaround that Gritstone has found for its cancer vaccines has been to target HLA peptide complexes on the tumor surface. "You open up the target landscape to all of the intracellular proteins in tumor cells, which includes things like mutated KRAS, which is only found in tumor cells." Going after mutant KRAS peptides presented by HLA molecules on the cell surface, he added, allows Gritstone's vaccine to have "exquisite solid tumor specificity." That's possible because HLA peptides present a snapshot of the intracellular proteome that the immune system can monitor for non-self proteins and attack, if needed.
Gritstone has seen some early success with this approach. In September, the company presented initial results from a Phase I/II trial of SLATE-KRAS or an earlier version of the vaccine SLATE v1 combined with Bristol Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) and its anti-CTLA-4 antibody Yervoy (ipilimumab). Out of 38 patients with KRAS-mutated metastatic solid tumors, 31 had microsatellite stable colorectal cancer and non-small cell lung cancer with detectable mutant KRAS ctDNA, and in this subset of patients, there was a 38 percent molecular response with either SLATE-KRAS or SLATE v1 combined with the checkpoint inhibitors.
Both treatments in the Gritstone-NCI study will target mutant-KRAS HLA peptides. The trial will build on Rosenberg's previous work showing efficacy of autologous TCR T-cell therapy to target those peptides. Preclinical studies have similarly shown that a cancer vaccine can augment that approach.
Patients in the trial will undergo the process of receiving the autologous T-cell therapy, meaning their own cells will be collected, modified, and re-infused. At the same time, study participants will receive the SLATE-KRAS vaccination. The hope is that the addition of the vaccine will extend the life of the modified T cells while also generating a T-cell response to the vaccine, creating a synergistic effect and leading to robust responses in patients.
"Persistence of T cells is a perennial challenge, particularly in solid tumor cell therapy," said Allen. The T cells "are there for a week or two weeks, but then they start to disappear from circulation. … We hope to stimulate the number of T cells and perhaps the activity of those T cells such that there will be more of them around for longer with high levels of activity and tumor-killing function, which, of course, may then have therapeutic benefit."
An advantage of targeting KRAS with immunotherapy versus a small molecule, according to Allen, is that it's more difficult for the cell to become resistant. Because KRAS is a driver mutation, the cell can't simply drop the mutation, or it stops being a tumor cell. Thus, it remains accessible to immunotherapy. Targeting KRAS with a small molecule drug only inhibits the activity of the receptor rather than killing the cell, leaving room for the tumor to bypass growth pathways that are inhibited by the drug. "With immunotherapy, we're not just about inhibiting growth, we're about destroying everything that's got that target on the surface, and that's the attraction here of KRAS," said Allen.
The one downside of this approach, Allen said, is that only one specific type of HLA will present the KRAS G12V and G12D antigens that are of interest in this study. That means that in order to be eligible for the trial, patients will need to have one of those KRAS mutations as well as the correct HLA allele, which Allen said is found in 20 percent to 40 percent of the population. For colon cancer, he estimated that around a third has a KRAS-mutated tumor, with two-thirds of those mutated tumors harboring KRAS G12D or G12V aberrations, specifically.
"In pancreatic cancer, the stats are more favorable because actually 97 percent of pancreatic cancer has a KRAS mutation and again mostly G12D and G12V," said Allen. "Then, you take your HLA cut and that's the population that's eligible for this therapeutic."
Unfortunately, that leaves a lot of patients without an option for this particular type of therapy. "It's not a natural law that every patient must have a clonal neoantigen on their tumor cell surface," Allen said.
Gritstone is hoping to meet the needs of the remaining patients with a line of personalized cancer vaccines, dubbed Granite, or an off-the-shelf product targeting a different antigen commonly found on tumors. "There is hope for every patient," Allen said.
Emeryville, California-based Gritstone doesn't yet have commercialization plans for this KRAS-targeted cancer vaccine and TCR T-cell therapy combination, as the trial with the NCI is just beginning. Delivering the cancer vaccine through an intramuscular shot, similar to the COVID-19 vaccines, will likely be the simplest part of the treatment, Allen said.
While manufacturing and delivering the autologous cell therapy component is more involved, Allen noted that the pathway paved by other companies like Gilead's Kite Therapeutics offers a model to follow. Allen said he was not aware of a commercial partner yet for the NCI's T-cell therapy but remained optimistic that a partner may emerge if the combination therapy shows meaningful efficacy in this trial.