Antigen-specific immunotherapies for acute myeloid leukemia

Abstract

Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody-drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard "3 ϩ 7"-based chemotherapy have remained unsatisfactory in many patients. Learning Objectives• To gain an overview of current clinical results with antigenspecific immunotherapies for acute myeloid leukemia • To become familiar with recent advances and evolving treatment concepts in the field of antigen-specific immunotherapy for acute myeloid leukemia and to appreciate the challenges in the clinical translation of these therapeutic strategies Conceptually, antigen-specific immunotherapies offer a versatile means of eliminating tumor cells with limited nonspecific toxicities. For many human cancers, including some hematological malignancies, such therapies have emerged as important components of curative treatment algorithms. 1-3 Success has been more modest for acute myeloid leukemia (AML). Nonetheless, among the few drugs that have shown to improve survival in recent randomized trials is the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO). The clinical experience with GO provides the strongest glimpse thus far of the potential value of antigen-targeted therapies for AML. Here, we review the results of efforts with antibodies and other antigen-directed passive and active immunotherapies in AML and summarize evolving treatment strategies for this disease.

Acute myeloid leukemia: 2016 Update on risk‐stratification and management

“…GO is a conjugate of an anti-CD33 monoclonal antibody and the cytotoxic agent, calechiamicin, the cell surface antigen CD33 being expressed in >90% of patients with AML [64]. Use of GO prior to 7 1 3 [65], its addition to low dose cytarabine (LDAC) in older patients [66], or its use alone in patients in remission [67] has not appeared successful.…”

“…Antibody-drug conjugates: nonuniform conjugation of the antibody in GO to the toxin calechiamicin results in labeling of only 50% of the antibody with the toxin [64,84]. Furthermore GO is a substrate for molecules that pump GO out of AML cells [ 64,84]. SGN-CD33a is designed to circumvent these limitations, has been studied as a single agent and in combination with azacitidine or 3 1 7 and a trial randomizing patients to 3 1 7 1/-SGNCD33a will soon begin enrollment.…”

“…SGN-CD33a is designed to circumvent these limitations, has been studied as a single agent and in combination with azacitidine or 3 1 7 and a trial randomizing patients to 3 1 7 1/-SGNCD33a will soon begin enrollment. A problem with BiTE and CAR therapy in AML is that unlike the case with ALL where such therapy has produced remissions in cases where none were expected, CD33 (or CD123) is also expressed on normal hematopoietic cells [64] and hence use of CAR T cells may mandate subsequent allogeneic HCT transplantation or introduction of "suicide genes". Although improved long-term outcomes with GO in some patients suggest CD33 is expressed in at least some patients on AML stem cells, whose elimination is thought crucial for cure in some patients, the relation between CD33 and AML stem cells awaits further elucidation [85].…”

Az akut myeloid leukaemia gyógyszeres kezelése. Jelenlegi lehetőségek, jövőbeli kilátások

“…Az innovatív és immunterápiával átütő eredmények eddig nem szület-tek. Az AML kezelésében betöltött helyük és szerepük megállapításához még hosszú idő (legalább 5-10 év) szükséges [34,35].…”

Fludarabine and Cytarabine Combination in the Induction of Adult Patients with Acute Myeloid Leukaemia

“…Over the last 30 years several alternative approaches have been explored with disappointing findings [2,3,4,5]. The management of patients not candidates for intensive regimens is even more difficult, and the therapeutic association between fludarabine and cytarabine (FLA) has been proposed in this clinical setting [6,7,8].…”