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The challenges of checkpoint inhibition in the treatment of multiple myeloma.

ABSTRACT: Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15?years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. While checkpoint inhibitors are effective in prolonging overall survival in some patients with advanced solid cancers and Hodgkin lymphoma, they have not demonstrated significant activity as a single agent in MM. In fact the combination of checkpoint inhibitors with IMiDs was recently found to increase the risk of death in myeloma patients. These challenges highlight the need for a better understanding of immune dysregulation in myeloma patients, and the mechanisms of action of- and resistance to- checkpoint inhibitors. In this review, we summarize immune dysfunction in patients with MM, and review the preclinical and clinical data regarding checkpoint inhibitors in myeloma. We conclude by proposing strategies to improve the efficacy and safety of checkpoint inhibitors in this population.

SUBMITTER: Paul B

PROVIDER: S-EPMC6309858 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The challenges of checkpoint inhibition in the treatment of multiple myeloma.

Paul Barry B Kang Shuqi S Zheng Zhihong Z Kang Yubin Y

Cellular immunology 20181013

Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15 years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. ...[more]

PMID: 30342750

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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:Whereas the treatment of MM was dependent solely on alkylating agents and corticosteroids during the prior three decades, the landscape of therapeutic measures to treat the disease began to expand enormously early in the current century. The introduction of new classes of small-molecule drugs, such as proteasome blockers (bortezomib and carfilzomib), immunomodulators (lenalidomide and pomalidomide), nuclear export inhibitors (selinexor), and histone deacetylase blockers (panobinostat), as well as the application of autologous stem cell transplantation (ASCT), resulted in a seismic shift in how the disease is treated. The picture changed dramatically once again starting with the 2015 FDA approval of two monoclonal antibodies (mAbs) - the anti-CD38 daratumumab and the anti-SLAMF7 elotuzumab. Daratumumab, in particular, has had a great impact on MM therapy and today is often included in various regimens to treat the disease, both in newly diagnosed cases and in the relapse/refractory setting. Recently, other immunotherapies have been added to the arsenal of drugs available to fight this malignancy. These include isatuximab (also anti-CD38) and, in the past year, the antibody-drug conjugate (ADC) belantamab mafodotin and the chimeric antigen receptor (CAR) T-cell product idecabtagene vicleucel (ide-cel). While the accumulated benefits of these newer agents have resulted in a doubling of the disease's five-year survival rate to more than 5 years and improved quality of life, the disease remains incurable. Almost without exception patients experience relapse and/or become refractory to the drugs used, making the search for innovative therapies all the more essential. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and on the horizon, including naked mAbs, ADCs, bi- and multi-targeted mAbs, and CAR T-cells. Emphasis is placed on the benefits of each along with the challenges that need to be overcome if MM is to be considered curable in the future.

Dataset Information

The challenges of checkpoint inhibition in the treatment of multiple myeloma.

Publications

The challenges of checkpoint inhibition in the treatment of multiple myeloma.

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