Invited reviewImmunotherapy in adult acute leukemia
Introduction
In this review, we focus on immunotherapy for acute lymphoblastic leukemia (ALL), and as far as available, acute myeloid leukemia (AML). Acute promyelocytic leukemia will not be discussed, as the treatment approach differs largely from both other entities and is discussed elsewhere. ALL and AML remain two major challenges for hematologists when it comes to cure. Roughly around half of these patients will ultimately relapse and die of their disease [1], [2]. In ALL, complete remission (CR) rate after salvage chemotherapy are low and ranges between 25 and 45% [2], [3], with most of these patients ultimately dying, resulting in a lot of room for improvement. A positive minimal residual disease (MRD) status is considered a negative predictive factor and also as an established marker for relapse in ALL [4]. The same trend seems to emerge for AML [5], [6]. Immunotherapy can be used to modify otherwise inevitable relapse in these scenarios.
The definition of immunotherapy varies slightly from one publication to another. In the treatment of leukemias, allogeneic hematopoietic stem cell transplantation (HSCT) is certainly its most classical example, based on cellular graft versus leukemia effect that can lead to cure, with graft versus host disease (GvHD) as its most feared complication. The definition can include the use of monoclonal antibodies such as anti-CD20 (rituximab), or can be defined as using the hostβs own cellular immunity to fight the underlying disease. This is done either by enhancing the hostβs immune system or suppressing negative regulators, depending on the targeted function, as T cells are known to play a major role in tumor surveillance [7]. In this review, we aim to focus on the more recent immunotherapy approaches; especially cell-based or modalities using preexisting host T-cells. We will concentrate on treatments already available, but we will also give an outlook on upcoming ones. With these new agents and cell-based therapies, a whole new spectrum of complications is emerging, a challenge for patients and their hematologists to deal with. Main challenges are cytokine release syndrome (CRS) and neurological complications. At the moment, mechanisms underlying these syndromes are not completely understood. Consequently, their ideal management is yet to be defined. For now, immunotherapy in acute leukemia is used in the relapse or MRD positive setting, aiming at a population with a very bad-risk profile.
Section snippets
Gemtuzumab ozogamicin
GO is an anti-CD33 antibody linked to calicheamicin, a toxin inducing DNA double-strand breaks. The drug was FDA approved in 2000 for elderly patients with relapsing AML [8], but was thereafter withdrawn from the market in 2010 when it failed to prove its efficacy in younger patients [9]. However, it seems that at least for a subset of patients, GO added to chemotherapy is able to improve outcome [10]. Because of heterogeneous anthracycline schedules and cumulative doses, this question cannot
Discussion
The current use of immunotherapy in acute leukemia is reserved for patients with either relapse of their disease, a refractory status or MRD positivity. Of note, despite this high risk profile, current available immunotherapy treatments showed efficacy. In future use, there is an interest to move at least part of the less dangerous immunotherapeutic approaches to frontline treatment, in order to improve outcome of patients with acute leukemia. These approaches are more developed for ALL than
Acknowledgements
The authors thank Roger Guindon for the realization of the figures. ML is supported by DKTK (L660) and DFG (CRC992, C04).
References (107)
- et al.
Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL)
Hematol. Oncol. Clin. North Am.
(2000) - et al.
Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation
Blood
(2012) - et al.
Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL)
Blood
(2009) - et al.
A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia
Blood
(2013) - et al.
Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials
Lancet Oncol.
(2014) - et al.
The past and future of CD33 as therapeutic target in acute myeloid leukemia
Blood Rev.
(2014) - et al.
Acute myeloid leukemia stem cells and CD33-targeted immunotherapy
Blood
(2012) - et al.
Antibody-targeted chemotherapy with immunoconjugates of calicheamicin
Curr. Opin. Pharmacol.
(2003) - et al.
Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab
Mol. Immunol.
(2007) - et al.
Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study
Lancet Oncol.
(2012)
Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells
Mol. Immunol.
Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL
Blood
Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study
Lancet Oncol.
CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330
Blood
Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML
Blood
CTLA-4 can function as a negative regulator of T cell activation
Immunity
Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection
Blood
Antibody-modified T cells: CARs take the front seat for hematologic malignancies
Blood
Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies
Blood
Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans
Biol. Blood Marrow Transpant.: J. Am. Soc. Blood Marrow Transplant.
Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo
Mol. Ther.: J. Am. Soc. Gene Ther.
CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results
Blood
ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells
Blood
Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment
Mol. Ther.: J. Am. Soc. Gene Ther.
Toxicities of chimeric antigen receptor T cells: recognition and management
Blood
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Lancet
Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells
Blood
CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date
Blood
Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019)
Blood
Implications of minimal residual disease negative complete remission (MRD-CR) and allogeneic stem cell transplant on safety and clinical outcome of CD19-targeted 19β28z CAR modified T cells in adult patients with relapsed, refractory B-cell ALL
Blood
Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study
Blood
Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults
Blood
The PD-1-PD-L pathway in immunological tolerance
Trends. Immunol.
Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia
Blood
In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis
Blood
Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration
Cancer
Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse
Haematologica
Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse
Leukemia
Immune surveillance of tumors
J. Clin. Invest.
Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia
Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.
Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia
Leukemia lymphoma
Constitutive endocytosis and degradation of CD22 by human B cells
J. Immunol.
Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin's lymphoma: results of a phase I study
J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol.
Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia
Cancer
Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a CD22 monoclonal antibody
Am. J. Hematol.
Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia
N. Engl. J. Med.
Preclinical to clinical translation of antibody-drug conjugates using PK/PD modeling: a retrospective analysis of inotuzumab ozogamicin
AAPS J.
The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells
Leukemia
Hybrid antibodies can target sites for attack by T cells
Nature
BiTE: teaching antibodies to engage T-cells for cancer therapy
Curr. Opin. Mol. Ther.
Cited by (16)
Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study
2020, Leukemia ResearchCitation Excerpt :Long-term overall survival is especially poor for older adults with AML and ALL, therefore there is an unmet need for improved therapeutics in this population [6]. Emerging immunotherapies such as antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), chimeric antigen receptor T (CAR-T) cells, and immune checkpoint inhibitors represent novel approaches for patients with ALL or AML who previously relied on chemotherapy [7β9]. Blinatumomab, an anti-CD19 BiTE, and inotuzumab ozogamicin, an anti-CD22 ADC, are now approved for treatment of R/R B-cell ALL [10,11], and the anti-CD33 ADC gemtuzumab ozogamicin is approved for treatment of CD33-positive AML [12].
CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia
2022, Nature Communications