CD38 targeted treatment for multiple myeloma

Abstract

SouhrnAntigen CD38 je uniformně a vysoce exprimován na plazmatických buňkách a stal se tak ideálním cílem pro léčbu mnohočetného myelomu (MM) pomocí anti-CD38 cílených monoklonálních protilátek (mAbs). Nejdále ve vývoji je daratumumab, nicméně podobně slibných výsledků dosahuje i isatuximab, který cílí na zcela jiný epitop molekuly CD38. Anti-CD38 mAbs mají pleiotropní mechanizmus účinku, který je popisován i u jiných mAbs, nicméně zásadním, novým a specifickým mechanizmem je tzv. imunomodulační efekt díky depleci CD38 + imunosupresivních buněčných populací. Monoterapie anti-CD38 mAbs vede k odpovědím u asi 30 % silně předléčených MM pacientů. Jelikož je toxicita těchto látek minimální a mají odlišný mechanizmus účinku, jsou ideálním partnerem do kombinační léčby s běžně užívanými antimyelomovými léky. Daratumumab je schválen jako součást již 3 režimů u relabovaných pacientů s MM a jeho kombinace s lenalidomidem a dexametazonem je v současné době považována za nejlepší možnou léčbu relapsu nemoci, při níž bylo dosaženo bezprecedentního prodloužení mediánu doby bez progrese (Progression Free Survival -PFS), celkové léčebné odpovědi, i kvality odpovědí. Anti-CD38 mAbs se postupně posouvají i do léčby první linie. Stejně tak jsou s úspěchem zkoušeny u dalších plazmocelulárních dyskrazií (AL-amyloidóza), dalších hematologických malignit (akutní lymfoblastická leukemie -ALL, akutní myeloidní leukemie -AML, chronická lymfocytární leukemie -CLL), a dokonce u solidních nádorů či autoimunitních onemocnění. Léčba pomocí anti-CD38 mAbs znamená podobnou revoluci pro pacienty s MM, jako zavedení anti-CD20 mAbs u nemocných s CLL či non-hodgkinskými lymfomy a zcela jistě je velkou nadějí do budoucna směřující k možnosti vyléčení alespoň části nemocných s MM. Klíčová slova: akutní myeloidní leukemie -CD38 -daratumumab -isatuximab -mnohočetný myelom CD38 targeted treatment for multiple myeloma Summary CD38 antigen is highly and uniformly expressed on plasma cells and thus represents an ideal target for the treatment of multiple myeloma (MM) with anti-CD38 monoclonal antibodies (mAbs). Daratumumab is the most advanced anti-CD38 mAb in the clinical development with approval in several indications, nevertheless isatuximab that targets completely different epitope of CD38 molecule is also very promising drug. Anti-CD38 possess pleiotropic mechanism of action that have been described also in other mAbs, but quite specific, novel and very important seems to be the immunomodulatory effect provided by depletion of several CD38 + immunosuppressive immune cell populations. CD38-targeted mAbs induce partial response or better in approximately 30 % of heavily pre-treated myeloma patients as monotherapy. Based on their favourable toxicity profile and distinct mechanism of action, anti-CD38 mAbs represents very attractive partner to back-bone anti-myeloma drugs. Indeed, daratumumab is already approved as a part of three distinct combination regimens in relapsed setting. The combination of daratumumab with lenalidomide and dexamethasone is cons...

Targeted therapy for multiple myeloma: an overview on CD138-based strategies

“…Accordingly, most preclinical and clinical MM studies to date have focused on the key immunotherapy antigens BCMA, CD38 and SLAMF7, with the latter two being the target of three already FDA-approved mAbs. BCMA, CD38 and SLAMF7 represent three key antigens in the biology of MM; the first plays a key role in B cell maturation and differentiation into PCs and is upregulated in disease progression from MGUS to SMM and active MM ( 15 ); the second is uniformly expressed on PCs and is involved in modulating immune cell activation and migration ( 9 ), while the latter is involved in the development of immune system and promotes PCs proliferation and growth ( 13 ). Given its central role in MM biology, restricted expression on normal PCs but strong upregulation on malignant cells, BCMA has become the most common target of various therapeutic strategies, each associated with logistical challenges and unique toxicities.…”

“…To achieve a safer and durable response in MM patients several studies have identified key antigens overexpressed on malignant PCs essential for MM progression, and innovative targeted therapeutic strategies have been developed against them, mainly based on monoclonal antibodies (mAbs), immunoconjugates, synthetic peptides, and adaptive cellular therapies (see below). In addition to the widely studied MM-related antigens CD38 ( 9 – 11 ) and signaling lymphocyte activation molecule F7 (SLAMF7) ( 12 – 14 ), against which three mAbs have already received FDA approval for clinical use ( 10 , 14 ), and the B-cell maturation antigen (BCMA) ( 15 , 16 ), there is growing evidence for the key role of Syndecan1 (CD138 or SDC1), a transmembrane heparan sulfate proteoglycan (HPSG), in MM tumorigenesis ( 17 – 19 ). CD138 is highly expressed on malignant PCs and is involved in several cellular pathways responsible for their growth, survival, and proliferation by binding many growth factors and proteins in the extracellular matrix (ECM) ( 17 , 20 ).…”

Risk of Severe Infections Secondary to the Use of Targeted Therapies in Hematological Malignancies

“…The CD38 antigen represents a frequently expressed antigen on plasma cells which makes them an excellent target for treatment in multiple myeloma (MM) by anti-CD38 directed agents [76]. Daratumumab, an anti-CD38 antibody, has demonstrated efficacy in MM by inducing Fc-mediated cell lysis by cell-mediated toxicity and complement activation [77].…”

Risk of Infections Secondary to the Use of Targeted Therapies in Hematological Malignancies

“…The CD38 antigen represents a frequently expressed antigen on plasma cells, which makes them an excellent target for treatment in multiple myeloma (MM) by anti-CD38-directed agents [ 72 ]. Daratumumab, an anti-CD38 antibody, has demonstrated efficacy in MM by inducing Fc-mediated cell lysis by cell-mediated toxicity and complement activation [ 73 ].…”