Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions

Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results.

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Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions

International Journal of Molecular Sciences ◽

10.3390/ijms23020904 ◽

2022 ◽

Vol 23 (2) ◽

pp. 904

Author(s):

Emma Verheye ◽

Jesús Bravo Melgar ◽

Sofie Deschoemaeker ◽

Geert Raes ◽

Anke Maes ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Ex Vivo ◽

Adoptive Cell Therapy ◽

Bone Marrow Niche ◽

Future Directions ◽

The Past ◽

Dc Vaccines ◽

Antigen Presenting

Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.

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Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.174 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 174-174

Author(s):

Nicholas J. Vogelzang ◽

Philip W. Kantoff ◽

Mark C. Scholz ◽

Jeffrey L. Vacirca ◽

Shaker R. Dakhil ◽

...

Keyword(s):

Performance Status ◽

Specific Antigen ◽

Cellular Immunotherapy ◽

Castration Resistant Prostate Cancer ◽

Phase 3 ◽

Castration Resistant ◽

Visceral Metastases ◽

Antigen Presenting ◽

Post Hoc ◽

Clinical Trial Information

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]

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Immunotherapy Using Dendritic Cells against Multiple Myeloma: How to Improve?

Clinical and Developmental Immunology ◽

10.1155/2012/397648 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 14

Author(s):

Thanh-Nhan Nguyen-Pham ◽

Yoon-Kyung Lee ◽

Hyeoung-Joon Kim ◽

Je-Jung Lee

Keyword(s):

Multiple Myeloma ◽

Dendritic Cells ◽

Myeloma Cell ◽

Cellular Immunotherapy ◽

Immune Effector ◽

Effector Cells ◽

Good Target ◽

Target Disease ◽

Antigen Presenting ◽

Dying Cells

Multiple myeloma (MM) is a good target disease in which one can apply cellular immunotherapy, which is based on the graft-versus-myeloma effect. This role of immune effector cells provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM. Current isolated idiotype (Id), myeloma cell lysates, myeloma dying cells, DC-myeloma hybrids, or DC transfected with tumor-derived RNA has been used for immunotherapy with DCs. Immunological inhibitory cytokines, such as TGF-β, IL-10, IL-6 and VEGF, which are produced from myeloma cells, can modulate antitumor host immune response, including the abrogation of DC function, by constitutive activation of STAT3. Therefore, even the immune responses have been observed in clinical trials, the clinical response was rarely improved following DC vaccinations in MM patients. We are going to discuss how to improve the efficacy of DC vaccination in MM.

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Enteric Fever Diagnosis: Current Challenges and Future Directions

Pathogens ◽

10.3390/pathogens10040410 ◽

2021 ◽

Vol 10 (4) ◽

pp. 410

Author(s):

Durga P. Neupane ◽

Hari P. Dulal ◽

Jeongmin Song

Keyword(s):

Diagnostic Tests ◽

Enteric Fever ◽

Asymptomatic Carrier ◽

Diagnostic Methods ◽

Effective Control ◽

Future Directions ◽

Clinical Presentations ◽

Global Spread ◽

Life Threatening ◽

Pros And Cons

Enteric fever is a life-threatening systemic febrile disease caused by Salmonella enterica serovars Typhi and Paratyphi (S. Typhi and S. Paratyphi). Unfortunately, the burden of the disease remains high primarily due to the global spread of various drug-resistant Salmonella strains despite continuous advancement in the field. An accurate diagnosis is critical for effective control of the disease. However, enteric fever diagnosis based on clinical presentations is challenging due to overlapping symptoms with other febrile illnesses that are also prevalent in endemic areas. Current laboratory tests display suboptimal sensitivity and specificity, and no diagnostic methods are available for identifying asymptomatic carriers. Several research programs have employed systemic approaches to identify more specific biomarkers for early detection and asymptomatic carrier detection. This review discusses the pros and cons of currently available diagnostic tests for enteric fever, the advancement of research toward improved diagnostic tests, and the challenges of discovering new ideal biomarkers and tests.

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Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma

Blood ◽

10.1182/blood-2005-11-4541 ◽

2006 ◽

Vol 107 (9) ◽

pp. 3492-3494 ◽

Cited By ~ 106

Author(s):

Shigesaburo Miyakoshi ◽

Masahiro Kami ◽

Koichiro Yuji ◽

Tomoko Matsumura ◽

Masaaki Takatoku ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Effects ◽

Gastrointestinal Symptoms ◽

Japanese Patients ◽

The United States ◽

Underlying Disease ◽

Pulmonary Complications ◽

Bortezomib Treatment ◽

Toranomon Hospital ◽

Life Threatening

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.

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A phase 1 study of RTX-321, an engineered red blood cell as an artificial antigen-presenting cell expressing HLA-A*02 with the HPV-16 E7 peptide and 4-1BB ligand with membrane-bound IL-12 for the treatment of HPV 16-positive cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps2664 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS2664-TPS2664

Author(s):

Johanna C. Bendell ◽

Alexander I. Spira ◽

Ramez Nassef Eskander ◽

Ezra E.W. Cohen ◽

Geoffrey Kuesters ◽

...

Keyword(s):

Head And Neck ◽

Dose Escalation ◽

Cell Expansion ◽

Phase 1 ◽

Costimulatory Molecule ◽

Cellular Immunotherapy ◽

Tumor Control ◽

Hpv 16 ◽

Artificial Antigen ◽

Antigen Presenting

TPS2664 Background: High-risk strains of HPV (HPV 16/18) have been associated with the development of multiple cancers, and the associated viral antigens are validated targets from immunotherapy approaches. We engineered red blood cells into allogeneic, off-the-shelf, artificial antigen-presenting cells (aAPCs) that express a human papillomavirus (HPV) 16 E7 peptide bound to human leukocyte antigen (HLA)-A*02:01, the costimulatory molecule 4-1BB ligand (L), and the cytokine interleukin (IL)-12 on the cell surface. This aAPC, RTX-321, activated HPV specific T-cells and promoted effector function in vitro. In animal models using a murine surrogate system, this aAPC approach resulted in robust antigen-specific T-cell expansion, NK cell expansion, tumor control, memory formation and antigen spreading, which led to a broad and robust antitumor immune response . The presence of 4-1BBL and IL-12 induced minimal toxicities in these models due to restriction of the biodistribution of the aAPC to the vasculature and spleen. RTX-321 is a potential in vivo cellular immunotherapy for treating HPV 16-positive cancers including cervical, head and neck and anal cancers. Methods: The RTX-321-01 study is a phase 1 multi-center, dose-escalation study of RTX-321 administered intravenously every 3 weeks in HLA-A*02:01-positive patients with relapsed or refractory HPV 16-positive cancers of the cervix or anal canal, or squamous cell cancers of the head and neck (HNSCC). Patients with cervical cancer or HNSCC will undergo testing for the presence of the HPV 16 virus or provide confirmation from archival tumor tissue prior to enrollment. Patients with anal cancer will not be required to have prospective determination of HPV 16-positive status prior to enrollment given the high incidence in this indication (approximately 80-85 percent of anal cancers). Approximately 18 patients will be enrolled across dose level cohorts to identify the recommended phase 2 dose (RP2D) of RTX-321, followed by RP2D expansion cohorts in specific indications. The starting dose is 1 billion (1x109) cells administered intravenously every 3 weeks (Q3W) and the dose will escalate by half-log increments, following a Bayesian logarithmic regression model (BLRM) with overdose control. Translational studies will investigate the activation and expansion of HPV16 E7 antigen-specific responses as well as broad innate and adaptive responses in multiple peripheral blood samples over the first 3 cycles of therapy as well as in optional paired tumor biopsies. At this time, the study is open and enrolling patients in the first dose escalation cohort (NCT04672980). Clinical trial information: NCT04672980.

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