ASCO Spotlight With Kim A. Reiss, MD, on CAR Macrophages and Other Developments in Pancreatic Cancer

Kim A. Reiss, MD, discussed with Evidence-Based Oncology™ (EBO) pancreatic cancer research presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in June 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. Reiss is assistant program director of the Hematology/
Oncology Fellowship Program and assistant professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia.

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

Reiss: One of the things that we worried about when we opened the study is whether [patients] 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 who were stable on the chemotherapy they were receiving.¹ 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 enthusiastic and interested. In fact, we enrolled all 84 patients at only the University of Pennsylvania in less than 3 years. 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 [who had toxicity] with niraparib [Zejula], 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 reasonable thing to ask of a patient to do. And for those who do well and are on therapy for a long time, the [adverse] 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 [will] open the door to explore maintenance for a broader population than for just the small number of patients with BRCA and PALB2 variants.

EBO: Can you discuss the CAR macrophage data you presented
during ASCO?²

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

This particular study looks at a [human epidermal growth factor receptor] HER2-directed CAR. Patients received GCSF [granulocyte colony-stimulating factor] and they then underwent 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 [using] a HER2-directed CAR, so as you can imagine, these are patients with HER2-positive solid tumors of any variety—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 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, [and the other was] their ability to recruit T cells to cause inflammation and hopefully in that way 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 [presented at ASCO reviews] the first 7 patients who 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 may get 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, but will be answered hopefully by the next steps in this study, is 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 other questions are, do they stay, how long do they stay, and 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 those questions as well.

[The product is] really cool. They ship it back to Penn, they take a third of the product and label it with zirconium 289, and then we do the whole infusion at the same time that the product gets put back all together, and then they image these patients and you can see areas where, hopefully, the macrophages are hanging out and then how long they’re there. It’s very exciting. 

References
1. Reiss KA, Mick R, Teitelbaum UR, et al. A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC). J Clin Oncol. 2022;40(suppl 16):4021. doi:10.1200/JCO.2022.40.16_suppl.4021
2. Reiss KA, Yuan Y, Ueno NT, et al. A phase 1, first-in-human (FIH) study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2 overexpressing solid tumors. J Clin Oncol. 2022;40(suppl 16):TPS2677. doi:10.1200/JCO.2022.40.16_suppl.TP22677