ASCO 2023 | Tumor vaccines, oncolytic viruses and CAR T
J. Randolph Hecht, MD, UCLA Santa Monica Medical Center, Santa Monica, CA, discusses immunotherapy approaches in solid tumors, including tumor vaccines as well as CAR T-cell therapies. In the vaccine field, targeting KRAS is an area of ongoing interest and has been shown to elicit an immune response. In addition, Prof. Hecht touches on CAR T-cell therapies in solid tumors and associated challenges including efficacy and approaches to mitigate off-target toxicity. This interview took place at the American Society of Clinical Oncology (ASCO) 2023 Annual Congress in Chicago, IL.
These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.
Transcript (edited for clarity)
You know, unfortunately, standard checkpoint inhibitors have not been helpful in the 97% of patients who have proficient DNA mismatch repair. And there are a lot of different ways that we’re trying to kind of, you know, to overcome whatever these immunosuppressive pathways are. Probably you need something. But clearly that’s not enough in this large group of patients...
You know, unfortunately, standard checkpoint inhibitors have not been helpful in the 97% of patients who have proficient DNA mismatch repair. And there are a lot of different ways that we’re trying to kind of, you know, to overcome whatever these immunosuppressive pathways are. Probably you need something. But clearly that’s not enough in this large group of patients. And there are several different ways that we’re looking at this.
One has been tumor vaccines. Tumor vaccines have been looked at for many decades. But really because of the revolution in sequencing and also computing power that allows the prediction of immunogenic antigens that might be that might be expressed that we really are really revisiting tumor vaccines. There are several there’s one against KRAS, G, R and D, which is the Eli 001, which will be presented here by Eileen O’Reilly, seems to at least have immune responses in that group of patients.
I’m involved with a trial that’s called GRANITE from a company called Gritstone, which is a personalized vaccine. And this is a large randomized phase two that’s looking at patients are randomized in the maintenance setting. So most people who have first-line metastatic colorectal cancer get an oxaliplatin-based therapy, but they can only be on so long because of neuropathy. So they then go to maintenance, which is usually capecitabine in this case plus bevacizumab and then patients are randomized to capecitabine bevacizumab plus or minus this vaccine. The vaccine is actually interesting, taking advantage of a prime boost strategy of a chimp adenovirus, sort of like the AstraZeneca COVID vaccine together with a self-replicating mRNA and also the thing that’s interesting about this is that there’s local injection of a CTLA-4 to try to really prime the lymph nodes they’ve seen some at least ctDNA changes, which is something that you would hope to see and that’s the end point for this phase two. So stay tuned.
We’re very interested in CAR-T’s which are basically engineered T cells that have an artificial chimeric antigen receptor on them to a target, Usually a tumor associated antigen together with an activated T cell have revolutionized how we treat hematologic malignancies. And in fact there are at least five CAR-T’s that are approved. They’re very active and they cure patients who have incurable disease.
Unfortunately, in solid tumors, we have not really seen a lot of activity. So the problems are dual. One is lack of efficacy and where there hasn’t been necessarily persistence of the CAR-Ts and not enough efficacy. But even more important, there’s been a problem that bedevils immunotherapy, which is on target, off tumor toxicity, and CAR-T’s against CEA and mesothelin have shown significant toxicity. Now, one that I’m collaborating with a company called A2 has been looking at the idea of a logic-gated CAR-T. So what you’re really looking for is something that as we always are in oncology that differs between normal and tumor cells, this is a little bit different is that we’re looking for something that’s present in the tumor cell and I’m sorry present in normal cells and absent in tumor cells.
So what we’re looking at specifically is HLA, there’s lots of HLA and about 20% of of g.I cancers And we’ve presented this before and published this. We published this data showing that you can distinguish and we have an assay which is called XT Onco with Tempest that reliably distinguishes those patients who have loss of heterozygosity. And we have an ongoing trial which I’m running called BASECAMP in order to accrue those patients.
We’re really excited because the first treatment trial which is against CEA called EVEREST-1, dosed their first patient within the last month. There was just a press release. There was no untoward toxicity, which is one of the things we’re looking at and we’re very excited about this. This is also a modular platform so you can change what the HLA is and you can also change what the target is. The next one is mesothelin, which is expressed in a number of different cancers which include not not just pancreatic carcinoma which we’re interested in, but also ovarian and non-small cell lung cancer. So hopefully this will overcome this problem of on target off tumor toxicity.
Read more...
