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Article ; Online: Role of B cells in immune-related adverse events following checkpoint blockade.

Dhodapkar, Kavita M / Duffy, Alyssa / Dhodapkar, Madhav V

2023 Volume 318, Issue 1, Page(s) 89–95

Abstract: Blockade of immune checkpoints has transformed the therapy of several cancers. However, immune-related adverse events (irAEs) have emerged as a major challenge limiting the clinical application of this approach. B cells are recognized as major players in ...

Abstract	Blockade of immune checkpoints has transformed the therapy of several cancers. However, immune-related adverse events (irAEs) have emerged as a major challenge limiting the clinical application of this approach. B cells are recognized as major players in the pathogenesis of human autoimmunity and have been successfully targeted to treat these disorders. While T cells have been extensively studied as therapeutic targets of immune checkpoint blockade (ICB), these checkpoints also impact B cell tolerance. Blockade of immune checkpoints in the clinic is associated with distinct changes in the B cell compartment that correlate with the development of irAEs. In this review, we focus on the possible role of humoral immunity, specifically human B cell subsets and autoantibodies in the pathogenesis of ICB-induced irAEs. There remains an unmet need to better understand the T:B cell cross talk underlying the activation of pathogenic B cells and the development of ICB-induced irAEs. Such studies may identify new targets or approaches to prevent or treat irAEs and improve the application of ICB therapy in cancer.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; B-Lymphocytes/pathology ; Autoimmunity ; Immune Checkpoint Inhibitors/adverse effects ; Autoantibodies ; Immunotherapy/adverse effects
Chemical Substances	Immune Checkpoint Inhibitors ; Autoantibodies
Language	English
Publishing date	2023-07-08
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13238
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Article ; Online: Role of B cells in immune‐related adverse events following checkpoint blockade

Dhodapkar, Kavita M. / Duffy, Alyssa / Dhodapkar, Madhav V.

Immunological Reviews. 2023 Sept., v. 318, no. 1 p.89-95

2023

Abstract: Blockade of immune checkpoints has transformed the therapy of several cancers. However, immune‐related adverse events (irAEs) have emerged as a major challenge limiting the clinical application of this approach. B cells are recognized as major players in ...

Abstract	Blockade of immune checkpoints has transformed the therapy of several cancers. However, immune‐related adverse events (irAEs) have emerged as a major challenge limiting the clinical application of this approach. B cells are recognized as major players in the pathogenesis of human autoimmunity and have been successfully targeted to treat these disorders. While T cells have been extensively studied as therapeutic targets of immune checkpoint blockade (ICB), these checkpoints also impact B cell tolerance. Blockade of immune checkpoints in the clinic is associated with distinct changes in the B cell compartment that correlate with the development of irAEs. In this review, we focus on the possible role of humoral immunity, specifically human B cell subsets and autoantibodies in the pathogenesis of ICB‐induced irAEs. There remains an unmet need to better understand the T:B cell cross talk underlying the activation of pathogenic B cells and the development of ICB‐induced irAEs. Such studies may identify new targets or approaches to prevent or treat irAEs and improve the application of ICB therapy in cancer.
Keywords	B-lymphocytes ; autoantibodies ; autoimmunity ; humans ; humoral immunity ; pathogenesis ; therapeutics
Language	English
Dates of publication	2023-09
Size	p. 89-95.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.13238
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Tissue-resident memory-like T cells in tumor immunity: Clinical implications.

Dhodapkar, Madhav V / Dhodapkar, Kavita M

Seminars in immunology

2020 Volume 49, Page(s) 101415

Abstract: Tissue-resident memory ( ... ...

Abstract	Tissue-resident memory (T
MeSH term(s)	Animals ; Cancer Vaccines/immunology ; Combined Modality Therapy ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunologic Memory ; Immunotherapy, Adoptive ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tumor Microenvironment/immunology
Chemical Substances	Cancer Vaccines ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2020-09-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2020.101415
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Article ; Online: Tregs protect against combination checkpoint blockade toxicity induced by TPH and B cell interactions.

Duffy, Alyssa / Azeem, Maryam I / Kanangat, Smriti / Yushak, Melinda / Lawson, David / Dhodapkar, Madhav V / Dhodapkar, Kavita M

The Journal of clinical investigation

2024

Language	English
Publishing date	2024-05-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI174724
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Article ; Online: Moving Immunoprevention Beyond Virally Mediated Malignancies: Do We Need to Link It to Early Detection?

Dhodapkar, Madhav V / Dhodapkar, Kavita M

Frontiers in immunology

2019 Volume 10, Page(s) 2385

Abstract: Vaccines can successfully prevent viral infections and have emerged as an effective strategy for preventing some virally mediated malignancies. They also represent our major hope for cost-effective reduction of the cancer burden. The concept that the ... ...

Abstract	Vaccines can successfully prevent viral infections and have emerged as an effective strategy for preventing some virally mediated malignancies. They also represent our major hope for cost-effective reduction of the cancer burden. The concept that the immune system mediates surveillance and editing roles against tumors is now well-established in murine models. However, harnessing the immune system to prevent human cancers that do not have a known viral etiology has not yet been realized. Most human cancers originate in a premalignant phase that is more common than the cancer itself. Many of the genetic changes that underlie carcinogenesis originate at this stage when the malignant phenotype is not manifest. Studies evaluating host response in human premalignancy have documented that these lesions are immunogenic, setting the stage for immune-based approaches for targeted prevention of human cancer. However, recent studies suggest that the hierarchy of T cell exhaustion and immune-suppressive factors have already begun to emerge in many preneoplastic states. These considerations underscore the need to link immune prevention to earlier detection of such lesions and to personalize such approaches based on the status of the pre-existing immune response.
MeSH term(s)	Animals ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/immunology ; Cell Transformation, Viral ; Chronic Disease ; Clinical Trials as Topic ; Disease Models, Animal ; Disease Susceptibility ; Early Detection of Cancer ; Humans ; Immunologic Surveillance ; Immunotherapy ; Mutation ; Neoplasms/diagnosis ; Neoplasms/etiology ; Neoplasms/prevention & control ; Precancerous Conditions/diagnosis ; Precancerous Conditions/etiology ; Precancerous Conditions/prevention & control ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome ; Virus Diseases/complications ; Virus Diseases/virology
Chemical Substances	Antigens, Neoplasm ; Cancer Vaccines
Language	English
Publishing date	2019-10-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.02385
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Article ; Online: Viral Immunity and Vaccines in Hematologic Malignancies: Implications for COVID-19.

Dhodapkar, Madhav V / Dhodapkar, Kavita M / Ahmed, Rafi

Cancer discovery

2020 Volume 2, Issue 1, Page(s) 9–12

Abstract: Patients with hematologic malignancies have increased susceptibility to viral infections and suboptimal immunologic responses to current vaccines due to both disease-associated and therapy-related immune dysfunction. These considerations may impact the ... ...

Abstract	Patients with hematologic malignancies have increased susceptibility to viral infections and suboptimal immunologic responses to current vaccines due to both disease-associated and therapy-related immune dysfunction. These considerations may impact the efficacy of emerging COVID-19 vaccines in this patient population as well and warrant the need to systematically study natural and vaccine-induced virus-specific immunity in these patients.
Language	English
Publishing date	2020-11-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2643-3230.BCD-20-0177
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Article ; Online: Viral Immunity and Vaccines in Hematologic Malignancies: Implications for COVID-19.

Dhodapkar, Madhav V / Dhodapkar, Kavita M / Ahmed, Rafi

Blood cancer discovery

2020 Volume 2, Issue 1, Page(s) 9–12

Abstract	Patients with hematologic malignancies have increased susceptibility to viral infections and suboptimal immunologic responses to current vaccines due to both disease-associated and therapy-related immune dysfunction. These considerations may impact the efficacy of emerging COVID-19 vaccines in this patient population as well and warrant the need to systematically study natural and vaccine-induced virus-specific immunity in these patients.
MeSH term(s)	COVID-19 ; COVID-19 Vaccines ; Hematologic Neoplasms ; Humans ; SARS-CoV-2 ; Virus Diseases/prevention & control
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2020-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3028898-8
ISSN	2643-3249 ; 2643-3230
ISSN (online)	2643-3249
ISSN	2643-3230
DOI	10.1158/2643-3230.bcd-20-0177
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Article ; Online: Co-evolution of Immune Response in Multiple Myeloma: Implications for Immune Prevention.

McCachren, Samuel S / Dhodapkar, Kavita M / Dhodapkar, Madhav V

Frontiers in immunology

2021 Volume 12, Page(s) 632564

Abstract: Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to ... ...

Abstract	Multiple myeloma (MM), a malignant neoplasm of plasma cells that reside in the bone marrow (BM), is universally preceded by a precursor state termed monoclonal gammopathy of undetermined significance (MGUS). Many individuals with MGUS never progress to MM or progress over many years. Therefore, MGUS provides a unique opportunity to surveil changes in the BM tumor microenvironment throughout disease progression. It is increasingly appreciated that MGUS cells carry many of the genetic changes found in MM. Prior studies have also shown that MGUS cells can be recognized by the immune system, leading to early changes in the BM immune environment compared to that of healthy individuals, including alterations in both innate and adaptive immunity. Progression to clinical MM is associated with attrition of T cells with stem memory-like features and instead accumulation of T cells with more terminally differentiated features. Recent clinical studies have suggested that early application of immune-modulatory drugs, which are known to activate both innate and adaptive immunity, can delay the progression to clinical MM. Understanding the biology of how the immune response and tumors coevolve over time is needed to develop novel immune-based approaches to achieve durable and effective prevention of clinical malignancy.
MeSH term(s)	Adaptive Immunity ; Bone Marrow/immunology ; Humans ; Immune Checkpoint Proteins/immunology ; Immunity, Innate ; Immunologic Surveillance ; Immunomodulation ; Monoclonal Gammopathy of Undetermined Significance/genetics ; Monoclonal Gammopathy of Undetermined Significance/immunology ; Multiple Myeloma/genetics ; Multiple Myeloma/immunology ; Multiple Myeloma/prevention & control ; Tumor Microenvironment
Chemical Substances	Immune Checkpoint Proteins
Language	English
Publishing date	2021-02-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.632564
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Article ; Online: Total shoulder arthroplasty in patients with Factor V Leiden.

Zehner, Katie M / Sanchez, Joshua G / Dhodapkar, Meera M / Modrak, Maxwell / Luo, Xuan / Grauer, Jonathan N

Journal of shoulder and elbow surgery

2024

Abstract: ... taken into account. Factor V Leiden (FVL), the most common inherited thrombophilia, is one ...

Abstract	Background: Anatomic and reverse total shoulder arthroplasty (TSA) are effective treatment options for end-stage glenohumeral osteoarthritis. However, consideration for pre-existing conditions must be taken into account. Factor V Leiden (FVL), the most common inherited thrombophilia, is one such condition that predisposes to a prothrombotic state and may affect perioperative and longer-term outcomes following TSA. Methods: Adult patients undergoing primary TSA for osteoarthritis indication were identified in the 2010 through October 2021 PearlDiver M157 database. Patients with or without FVL were matched at a 1:4 ratio based on age, sex, and Elixhauser Comorbidity Index. Ninety-day adverse events and five-year revision rates were assessed and compared with multivariable logistic regression and rank-log tests, respectively. Finally, the relative use and bleeding/clotting outcomes were assessed based on venous thromboembolic (VTE) prophylactic agents utilized, with categories defined as (1) warfarin, heparin, or direct oral anticoagulant (DOAC) or (2) aspirin/no prescriptions found. Results: Of 104,258 TSA patients, FVL was identified for 283 (0.27%). Based on matching, 1,081 patients without FVL and 272 patients with FVL were selected. Multivariable analyses demonstrated that those with FVL displayed independently greater odds ratios (ORs) of deep vein thrombosis (DVT, OR=9.50, p<0.0001), pulmonary embolism (PE, OR = 10.10, p<0.0001), and pneumonia (OR=2.43, p=0.0019). Further, these events contributed to the increased odds of aggregated minor (OR = 1.95, p=0.0001), serious (OR=6.38, p<0.0001), and all (OR=3.51, p<0.0001) adverse events. All other individual 90-day adverse events, as well as 5-year revision rates, were not different between the study groups. When compared to matched patients without FVL on the same anticoagulant agents, FVL patients on warfarin/heparin/DOAC agents demonstrated lesser odds of 90-day DVT and PE (OR=4.25, p<0.0001 and OR=2.54, p=0.0065) than those on aspirin/no prescriptions found (OR=7.64 and OR=21.95, p<0.0001 for both). Interestingly, those on VTE prophylactic agents were not at greater odds of bleeding complications (hematoma or transfusion). Discussion and conclusions: TSA patients with FVL present a difficult challenge to shoulder reconstruction surgeons. The current study highlights the strong risk of VTE that was reduced but still significantly elevated for those with stronger classes of VTE chemoprophylaxis. Acknowledging this risk is important for surgical planning and patient counseling, but also noted was the reassurance of similar 5-year revision rates for those with versus without FVL.
Language	English
Publishing date	2024-03-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	1170782-3
ISSN	1532-6500 ; 1058-2746
ISSN (online)	1532-6500
ISSN	1058-2746
DOI	10.1016/j.jse.2024.01.041
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Article ; Online: Immune Modulation in Hematologic Malignancies.

Dhodapkar, Madhav V / Dhodapkar, Kavita M

Seminars in oncology

2015 Volume 42, Issue 4, Page(s) 617–625

Abstract: The therapeutic potential of the immune system in the context of hematologic malignancies has long been appreciated particularly due to the curative impact of allogeneic hematopoietic stem cell transplantation (SCT). The role of immune system in shaping ... ...

Abstract	The therapeutic potential of the immune system in the context of hematologic malignancies has long been appreciated particularly due to the curative impact of allogeneic hematopoietic stem cell transplantation (SCT). The role of immune system in shaping the biology and evolution of these tumors is now well recognized. While the contribution of the immune system in anti-tumor effects of certain therapies such as immune-modulatory drugs and monoclonal antibodies active in hematologic malignancies is quite evident, the immune system has also been implicated in anti-tumor effects of other targeted therapies. The horizon of immune-based therapies in hematologic malignancies is rapidly expanding with promising results from immune-modulatory drugs, immune-checkpoint blockade, and adoptive cellular therapies, including genetically-modified T cells. Hematologic malignancies present distinct issues (relative to solid tumors) for the application of immune therapies due to differences in cell of origin/developmental niche of tumor cells, and patterns of involvement such as common systemic involvement of secondary lymphoid tissues. This article discusses the rapidly changing landscape of immune modulation in hematologic malignancies and emphasizes areas wherein hematologic malignancies present distinct opportunities for immunologic approaches to prevent or treat cancer.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Hematologic Neoplasms/immunology ; Hematologic Neoplasms/therapy ; Humans ; Immune System/immunology ; Immunomodulation/immunology ; Immunotherapy, Adoptive/methods
Chemical Substances	Antibodies, Monoclonal
Language	English
Publishing date	2015-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	189220-4
ISSN	1532-8708 ; 0093-7754
ISSN (online)	1532-8708
ISSN	0093-7754
DOI	10.1053/j.seminoncol.2015.05.009
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