Daratumumab induces cell-mediated cytotoxicity of primary effusion lymphoma and is active against refractory disease

ABSTRACT

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10–22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara’s effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.

KEYWORDS:

• Daratumumab
• primary effusion lymphoma (PEL)
• pomalidomide
• rituximab
• all-trans retinoic acid (ATRA)
• CD38
• antibody-dependent cell-mediated cytotoxicity (ADCC)
• complement-dependent cytotoxicity (CDC)
• kaposi sarcoma-associated herpesvirus (KSHV)
• leptomeningeal PEL

Acknowledgments

This study was supported by the intramural research program of the NCI, NIH. Some of the Dara used in this study was provided by Janssen Pharmaceuticals under a CRADA with the NCI. We would like to thank our patients and their families who contributed to this research.

Disclosure statement

R. Yarchoan reports receiving drug supply for laboratory research from Janssen Pharmaceuticals and CTI BioPharma. R. Yarchoan, K. Lurain, and R. Ramaswami report receiving research support from Celgene (now Bristol Myers Squibb) through CRADAs with the NCI and receiving drugs for clinical trials from Merck, EMD-Serono, Eli Lilly, and Janssen through CRADAs with the NCI. R. Yarchoan is a co-inventor on US Patent 10,001,483 entitled “Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers.” An immediate family member of R. Yarchoan is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis, and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). No potential conflicts of interest were disclosed by the other authors.

Data Availability

The data that support the findings of this study are presented in the main text or the supplementary material. Additional data that support the findings of this study are available from the corresponding author [R.Y.], upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2022.2163784

Additional information

Funding

This work was supported by the Intramural Research Program of the National Cancer Institute, NIH.