Hyperprogression During Immunotherapy: Teasing Out the Mechanism

The Fc receptor, which binds antibodies and is located on the membrane of immune cells, may mediate hyperprogressive disease in non-small cell lung cancer (NSCLC), according to the findings of a preclinical study published in Translational Cancer Mechanisms and Therapy.¹

Hyperprogression is a controversial term used to describe a tumor that rapidly grows during treatment with immune checkpoint blockade. Although studies have increasingly shown possible prevalence rates in various cancer types ranging from 9% to 29%, whether hyperprogression is a real clinical entity remains an area of debate.² The current preclinical study provides the first glimpse into a possible biological mechanism.

“I don’t think that at this moment we have a very clear answer, but this paper definitely showed some of the mechanism of how hyperprogression may occur,” Shumei Kato, MD, medical oncologist, UC San Diego Health, California, told Cancer Therapy Advisor. Although he was not involved in the current study, Dr Kato coauthored a key study that identified MDM2 amplification and EGFR mutations as potential biomarkers associated with hyperprogression.³ He said that while the current study is not “conclusive” in terms of the mechanism, “it’s definitely a step forward.”

To tease out a possible mechanism, study researchers began by assessing pretreatment tumor tissue samples from advanced NSCLC patients who received an immune checkpoint inhibitor. They found that all samples from patients with hyperprogressive disease (11 individuals) were enriched with a population of tumor-associated macrophages (TAMs). The TAMs had an M2-like CD163+CD33+PD-L1 phenotype, and compared with a set of 24 NSCLC patients without hyperprogressive disease, the frequency of the immunophenotype seen in patients with hyperprogressive disease was statistically significant (P <.0001).

The researchers recreated the M2-like CD163+CD33+PD-L1 phenotype seen in hyperprogressive patients in immunodeficient mouse models injected with human lung cancer cells and immunodeficient mouse models with patient-derived xenografts. Both immunodeficient mouse models were exposed to intact anti-PD-1, which led to tumor growth. Then the Fc portion of the anti-PD-1 antibody was cleaved and the remaining anti-PD-1 Fab fragment was administered to the immunodeficient mouse models and no tumor growth occurred.

Together, the observations suggest that the binding of the immune checkpoint inhibitor’s Fc domain with the Fc receptor on macrophages may lead to reprogramming of these cells to behave in an aggressive, protumor manner. Although these experiments may in part explain how hyperprogression occurs, whether the Fc domain and Fc receptor are actually involved requires further study.

“[The researchers] provide some supportive data that the Fc fragment of the antibody may be involved, but it’s just not detailed enough yet to say that for sure,” David Knorr, MD, PhD, Rockefeller University, New York, New York, told Cancer Therapy Advisor. Dr Knorr, who was not involved in the study, coauthored a corresponding commentary.⁴ He noted that a technical limitation of the study was the choice of using immunodeficient mouse models to test an immune therapy; other models, such as an immunocompetent mouse model, may have been better suited. Also, cleavage of the monoclonal antibody to produce the Fab fragments may have affected the trafficking of the drug to the tumor site. “Whether or not it’s truly an Fc-mediated mechanism is still unclear at this time,” he said.

“We still don’t know for sure whether or not hyperprogression is a defined clinical entity, but that doesn’t mean we shouldn’t keep studying it and trying to define potential mechanisms,” Dr Knorr added. “This [study] is a stepping stone in doing that.”

References

1. Lo Russo G, Moro M, Sommariva M, et al. Antibody–Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res. 2019;25(3):989-999.
2. Champiat S, Ferrara R, Massard C, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018;15(12):748-762.
3. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242-4250.
4. Knorr DA and Ravetch JV. Immunotherapy and hyperprogression: unwanted outcomes, unclear mechanism. Clin Cancer Res. 2019;25(3):904-906.