Dr Kim A. Reiss: There Are Several Exciting Developments in Pancreatic Cancer Research

Kim A. Reiss, MD, is assistant program director of the Hematology/Oncology Fellowship Program and assistant professor of medicine at the Hospital of the University of Pennsylvania.

Here she discusses pancreatic cancer research she presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting on quality of life for patients on investigational noncytotoxic chemotherapies and promising developments in chimeric antigen receptor macrophages (CAR-M) for use in solid tumors.

Transcript

What are the quality-of-life considerations for patients with advanced pancreatic cancer taking a PARP inhibitor with ipilimumab?

One of the things that we worried about when we opened the study is whether people would agree to do it. So we’re looking at an all-comer population, not a DDR [DNA damage repair]–specific population, and these were patients that were stable on the chemotherapy that they were receiving. And so one of the questions was: would these patients and their physicians be willing to discontinue effective chemotherapy in the face of a very lethal disease and jump into a noncytotoxic maintenance treatment? And the answer was an overwhelming, "yes."

Oncologists recommended patients try the study, and patients were very, very enthusiastically interested. In fact, we enrolled all 84 patients at only the University of Pennsylvania in under 3 years. So, there was a huge amount of interest in trying to get away from cytotoxic therapies.

My own experience on this, aside from the couple of patients who had toxicity with IPI [ipilimumab] that was grade 2 or 3, and some with niraparib, almost universally, patients shared that their life was better, that their quality of life was better, that they could do things that they weren’t able to do while on chemotherapy. That is one of the reasons that this strategy is so important for patients with pancreatic cancer. Perpetual chemotherapy is not a really reasonable thing to ask of a patient to do. And for those that do well, and are on therapy for a long time, the side effects accumulate—they’re more fatigued, they’re marrow suppressed, they get more neuropathy—and so we really need to do better. What this study hopefully has the potential to do is open the door to explore maintenance for a broader population than for just that small number of patients with BRCA and PALB2 variants.

Can you discuss the CAR macrophage data you are presenting at ASCO?

Historically, CAR [chimeric antigen receptor] T-cell therapy has not been effective in solid tumors, and so one of the questions that the CAR-M, the Carisma [Carisma Therapeutics] CAR-M macrophage is trying to answer is, could macrophages be used as an alternative to the CAR T cells to see if they have active efficacy in solid tumors?

This particular study looks at a HER2-directed CAR. So, patients received GCSF [granulocyte colony-stimulating factor] and they then undergo plasmapheresis with siphoning off of monocytes. Those are then grown up ex vivo into macrophages and are transduced with a HER2 CAR, and the product is then shipped back and thawed at bedside and reinfused into patients. This particular study again is a HER2-directed CAR, so as you can imagine, these are patients with HER2-positive solid tumors of any variety—so any solid tumor with a HER2 amplification either by IHC [immunohistochemistry] or by PCR [polymerase chain reaction] is admitted.

The reason that macrophages were chosen is that they actually spend a lot of time within tumors in the tumor microenvironment. They are a major antigen-presenting cell, and they also have direct cytotoxic effects, so there were 2 angles. One is the direct toxicity to the tumor of macrophages, but also their ability to recruit T cells to cause inflammation and hopefully in that way to be antitumor.

The primary end points of this particular study are feasibility and safety. The first question was: can we do it? Can we get enough monocytes from these heavily pretreated patients? And the second is: is it safe to put macrophages back into humans this way? The answer to both questions appears to be yes. The poster talks about the first 7 patients that were treated; we’ve now treated 9. There is not a lot of toxicity associated with this therapy; there is a brief cytokine release, and then a few patients up to grade 2 CRS [cytokine release syndrome] that resolves very quickly. Other than that, we’ve not seen much in the way of toxicity. And so the study will be moving forward.

One of the big questions that remains unanswered so far, but will be answered hopefully by the next steps in this study, are how long do these CAR-Ms last in tumor? We know by RNA scope that they do get there in some patients a day 8 and then at week 4. But the second question is, do they stay, how long do they stay, and also is there heterogeneity? Because we know that there’s HER2 heterogeneity, potentially in tumor, so are the macrophages heading only to certain areas?

In the second half of the study, we will be tagging part of the product with zirconium 289 and then taking PET-type images of these patients over a period of days and weeks after that to see if we can answer both of those questions as well.

That is a very exciting piece. It’s really cool. They ship it back to Penn, they take a third of the product and label it with this zirconium product, and then we do the whole infusion at the same time that the product gets put back all together, and then they image these folks and you can see areas where, hopefully, the macrophages are hanging out and then how long they're there. It’s very exciting.