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Checkpoint inhibition in myeloma.

ABSTRACT: Historically, attempts at cancer immunotherapy have emphasized strategies designed to stimulate or augment the immune system into action. In the past decade, a complementary approach has developed, that of releasing immune cells from inhibitory restraint. Discoveries in the fundamental biology of how immunity is regulated, how the immune system interfaces with malignancy, and how cancer cells may exploit these processes to evade detection have all been translated into the rapidly growing field of therapeutic immune checkpoint inhibition for cancer. Myeloma is a malignancy associated with significant immune dysfunction imparted both by the disease itself as well as by many of the immunosuppressive therapies that have been used in the past. The growing body of preclinical data regarding immunoregulatory mechanisms that appear active in myeloma has begun to be translated to clinical trials targeting these signaling axes. This review will attempt to summarize the current understanding of the basic biology of several immune checkpoint pathways that may be important in myeloma and provide an up-to-date overview of recent and ongoing clinical trials of immune checkpoint inhibitors in myeloma. Finally, several current challenges and possible future directions of immune checkpoint blockade in myeloma will be reviewed.

SUBMITTER: Benson DM

PROVIDER: S-EPMC6142496 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Checkpoint inhibition in myeloma.

Benson Don M DM

Hematology. American Society of Hematology. Education Program 20161201 1

Historically, attempts at cancer immunotherapy have emphasized strategies designed to stimulate or augment the immune system into action. In the past decade, a complementary approach has developed, that of releasing immune cells from inhibitory restraint. Discoveries in the fundamental biology of how immunity is regulated, how the immune system interfaces with malignancy, and how cancer cells may exploit these processes to evade detection have all been translated into the rapidly growing field o ...[more]

PMID: 27913525

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Project description:Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as "immune checkpoints") including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.

Project description:PurposeImmune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.Experimental designTreatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.ResultsUnexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.ConclusionsThese data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211-22. ©2016 AACRSee related commentary by Felices and Miller, p. 5161.

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Checkpoint inhibition in myeloma.

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Checkpoint inhibition in myeloma.

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