A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

TY - JOUR

T1 - A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

AU - Schieferdecker, Aneta

AU - Oberle, Anna

AU - Thiele, Benjamin

AU - Hofmann, Fabian

AU - Göthel, Markus

AU - Miethe, Sebastian

AU - Hust, Michael

AU - Braig, Friederike

AU - Voigt, Mareike

AU - Pein, Ute-Marie

AU - Nolte, Friedrich

AU - Haag, Friedrich

AU - Alawi, Malik

AU - Indenbirken, Daniela

AU - Grundhoff, Adam

AU - Bokemeyer, Carsten

AU - Bacher, Ulrike

AU - Kröger, Nicolaus

AU - Binder, Mascha

N1 - Copyright © 2016 American Society of Hematology.

PY - 2016/6/23

Y1 - 2016/6/23

N2 - Multiple myeloma is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization and next-generation sequencing assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared to autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. While some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fitted well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of multiple myeloma that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy.

AB - Multiple myeloma is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly disease-specific, strongly and stably expressed antigens. Here we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization and next-generation sequencing assisted antibody phage display to establish a highly myeloma-specific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared to autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. While some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fitted well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of multiple myeloma that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy.

U2 - 10.1182/blood-2015-10-676536

DO - 10.1182/blood-2015-10-676536

M3 - SCORING: Journal article

C2 - 27034429

VL - 127

SP - 3202

EP - 3214

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 25

ER -