Page 1779 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 102

IMMUNE CHECKPOINT BLOCKADE IN

HEMATOLOGIC MALIGNANCIES

Reid Merryman and Philippe Armand

INTRODUCTION manageable safety profile but also an unprecedented overall survival
5
benefit with significant rates of long-term survival. Beyond mela-
The acquisition of a malignant phenotype by a cell is accompanied noma, ipilimumab has also shown therapeutic benefit in prostate,
6–8
by many genetic and epigenetic changes. These changes result in the pancreatic, and nonsmall-cell lung cancer cancers. These results
generation of distinct antigens (“tumor neoantigens”), which can be sparked interest in using CTLA-4 blockade in the treatment of HMs.
potentially recognized by T-cell receptors (TCRs) and targeted by a In 2009, the first reported study, a phase 1 trial of ipilimumab in
cell-mediated immune response. T-cell activation is a complex and relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), dem-
carefully regulated process governed by stimulatory and inhibitory onstrated an 11% objective response rate (ORR). The response rate
signals from antigen presenting cells (APCs) and other cells in the was less notable than the duration of the two clinical responses—a
surrounding microenvironment. Many inhibitory and costimulatory complete response (CR) in a patient with diffuse large B-cell lym-
receptors, termed “immune checkpoints,” have now been identified. phoma (DLBCL) lasting 31 months and a partial response (PR) in
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Tumor cells are known to interfere with the normal operation of these a patient with follicular lymphoma (FL) lasting 14 months. Such
pathways, providing a critical mechanism by which they can evade durable responses with single agent therapy spurred interest in
immune destruction. Our understanding of both the normal regula- CTLA-4 blockade specifically and CBT in general within HMs.
tion of T-cell function and its dysregulation by malignant cells has There are ongoing trials of ipilimumab in myeloid and lymphoid
accelerated greatly in recent years, allowing therapeutic intervention malignancies (NCT01757639, NCT01896999, NCT01729806). In
at the level of the immune synapse. The clinical development of addition, ipilimumab has shown promise for the postallogeneic
immune checkpoint-blocking monoclonal antibodies (mAbs) now transplant relapse setting, where it may augment the graft-versus-
allows the therapeutic modulation of those pathways in vivo and the tumor (GVT) effect, as discussed later.
restoration of antitumor immune activity in patients. Already, anti- Importantly, early clinical results in HMs suggested that immune-
bodies for two targets—cytotoxic T lymphocyte-associated antigen related adverse events (irAEs) with ipilimumab are similar to those
4 (CTLA-4) and the programmed cell death protein 1 (PD-1) seen in solid malignancies. Continued observation and reporting will
pathway—have shown impressive efficacy in clinical trials. Several be necessary to ensure that rates of pneumonitis, colitis, dermatitis,
other targets are under investigation with promising preclinical and endocrinopathies, and other immune side effects are generally man-
early clinical results (Fig. 102.1). Checkpoint blockade therapies ageable in HMs, as they appear to be in solid malignancies.
(CBT) have been more extensively studied in solid malignancies, but
a small number of early phase studies have generated exciting results
in hematologic malignancies (HMs), particularly in Hodgkin lym- PROGRAMMED CELL DEATH PROTEIN 1
phoma (HL). Given those early results, and the well-known suscep-
tibility of many HMs to immunotherapy, illustrated by the success PD-1 is an inhibitory immune checkpoint receptor expressed on T
of allogeneic hematopoietic stem cell transplant (HSCT) across many cells and other lymphocytes. Like CTLA-4, PD-1 is upregulated
HM subtypes, there is today a real hope that CBT could profoundly upon T-cell activation. When bound to one of its two ligands
influence the treatment paradigms in HMs. (PD-L1 or PD-L2), it inhibits T-cell activation via phosphatase activ-
2
ity in a mechanism that appears to be distinct from that of CTLA-4.
In addition to CD8+ effector T cells, PD-1 is expressed on Tregs
CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN 4 where it promotes their proliferation and downregulation of immune
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responses. PD-1 is expressed on tumor-infiltrating lymphocytes
CTLA-4, an inhibitory receptor expressed on T cells, was the first across many different types of tumors, and its ligands PD-L1 and
immune checkpoint receptor to be targeted for immunotherapy. PD-L2 are upregulated in many different tumors. 10–12 In contrast to
Upon T-cell activation, CTLA-4 is generally upregulated, which CTLA-4, which regulates early phases of T-cell activation, the PD-1
results in the dampening of T-cell function through several mecha- pathway appears to be most important during the effector phase of
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nisms. First, CTLA-4 counteracts the costimulatory receptor CD28 T-cell activation that occurs within the tumor microenvironment.
by binding to their shared ligands CD80 and CD86 with greater It was therefore hoped that PD-1 blockade would provide a more
1
affinity. It triggers multiple inhibitory cell signaling pathways leading targeted immune-enhancing approach at a later stage of T-cell activa-
2,3
to T-cell anergy. Finally, it downregulates the function of T-helper tion and therefore result in lower rates of irAEs compared with
cells and enhances the action of regulatory T cells (Tregs) through CTLA-4 blockade.
1
mechanisms that are not yet fully understood. The multifactorial Like CTLA-4, PD-1 blockade showed important therapeutic
actions of CTLA-4 underpin its importance in maintaining immune activity in melanoma, where phase III studies have shown benefit
13
tolerance, which is demonstrated by the immune hyperactivation in heavily pretreated patients. Trials of PD-1 and PD-L1 block-
phenotype of the lethal CTLA-4 knockout mouse. 4 ade have also demonstrated benefit in nonsmall-cell lung cancer,
Given its fundamental role in immune tolerance, CTLA-4 was a RCC, and other solid malignancies. 14–16 Multiple mAbs against
natural target for testing the concept of immune checkpoint blockade; PD-1 and PD-L1 have been developed and are in different stages
however, the prospect of blocking CTLA-4 in humans also raised the of investigation. At this time, three PD-1 inhibitors—nivolumab
specter of significant autoimmune toxicity. In fact, clinical trials of (Bristol-Myers Squibb, Princeton, NJ, USA), pembrolizumab (Merck,
CTLA-4 blockade using the mAb ipilimumab (Bristol-Myers Squibb, Kenilworth, NJ, USA), and pidilizumab (CureTech, Yavne, Israel)—
Princeton, NJ, USA) in patients with melanoma showed not only a have been studied in published trials in HMs, with preliminary
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