Hiding the road signs that lead to tumor immunity

Schaer et al. discuss mechanisms of immune evasions by tumors, including the recent finding that CCL2 nitrosylation prevents T cell infiltration into tumors

Diabetes mellitus and risk of plasma cell and lymphoproliferative disorders in 94,579 cases and 368,348 matched controls

this research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (UAS) and supported by grants from Swedish Cancer Society (MB), Parker Institute of Cancer Immunotherapy Career Development Award (YD, UAS), International Myeloma Society Career Development Award, Paula and Rodger Riney Foundation, American Society of Hematology Clinical Research Training Institute Award and TREC Training Workshop R25CA203650 (PI: Melinda Irwin) (UAS). Copyright & Usage Copyright (c) 2022 Ferrata Storti Foundation Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Peer reviewe

Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response

A primary goal of cancer immunotherapy is to improve the naturally occurring, but weak, immune response to tumors. Ineffective responses to cancer vaccines may be caused, in part, by low numbers of self-reactive lymphocytes surviving negative selection. Here, we estimated the frequency of CD8+ T cells recognizing a self-antigen to be <0.0001% (∼1 in 1 million CD8+ T cells), which is so low as to preclude a strong immune response in some mice. Supplementing this repertoire with naive antigen-specific cells increased vaccine-elicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specific cells impaired functional benefit, most likely because of intraclonal competition in the irradiated host. We show that cells primed at precursor frequencies below this competitive threshold proliferate more, acquire polyfunctionality, and eradicate tumors more effectively. This work demonstrates the functional relevance of CD8+ T cell precursor frequency to tumor immunity and autoimmunity. Transferring optimized numbers of naive tumor-specific T cells, followed by in vivo activation, is a new approach that can be applied to human cancer immunotherapy. Further, precursor frequency as an isolated variable can be exploited to augment efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8+ T cells

Immunotherapy: A New Approach to Treating Multiple Myeloma with Daratumumab and Elotuzumab

OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of daratumumab and elotuzumab for the treatment of relapsed refractory multiple myeloma (RRMM). DATA SOURCES: A literature search of MEDLINE, PubMed, the US National Institutes of Health Clinicaltrials.gov, the Food and Drug administration, and relevant meeting abstracts was conducted using the terms daratumumab, elotuzumab, multiple myeloma, anti-CD38, HuMax-CD38, HuLuc63, SLAMF7, and anti-CS1 STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daratumumab and elotuzumab for MM were identified. DATA SYNTHESIS: Daratumumab (anti-CD38) and elotuzumab (anti-CS1) have been recently FDA approved for the treatment of RRMM after showing efficacy in clinical trials. Elotuzumab approval was based on phase III data, and daratumumab gained accelerated approval based on phase I/II trials. Daratumumab has demonstrated significant single-agent activity, with an overall response rate (ORR) of 36% in patients with a median of 4 prior lines of therapy. Elotuzumab has not been shown to have single-agent activity. But the efficacy of both these antibodies in combination with lenalidomide and dexamethasone in RRMM showed an ORR exceeding 80%. Tolerability of elotuzumab and daratumumab seems to be acceptable, with the most common adverse event being infusion reactions. CONCLUSION: Daratumumab and elotuzumab have shown encouraging results in RRMM that led to their FDA approval. Both are well tolerated with minimal toxicities. Phase III clinical trials will define optimal combination and place in therapy of daratumumab and elotuzumab

Inhibition of Chemokine Expression by Adenovirus Early Region Three (E3) Genes

Adenoviruses (Ad) have a variety of immunoregulatory genes, many of which are clustered in a 3.5-kb segment of DNA known as early region 3 (E3). Ad E3 codes for proteins that downregulate surface expression of class I major histocompatibility antigens and also inhibit tumor necrosis factor alpha (TNF-α)- and Fas-induced cytolysis. We were interested in determining whether chemokine production or activity might also be inhibited by Ad E3 and we have studied this function in a human astrocytoma cell line, U373. Astrocytes constitute a part of the blood-brain barrier, and chemokines (IP-10, IL-8, MCP-1-4, and MIPs) expressed by them may contribute to leukocyte infiltration within the brain during inflammation. When U373 cells are activated by the proinflammatory molecule TNF-α, the increase in chemokine MCP-1, IL-8, and IP-10 transcripts is blocked by a recombinant Ad expressing the E3 genes under cytomegalovirus promoter control. Comparable Ads expressing green fluorescent protein in place of E3 have no effect on these chemokines. Ads also have been extensively studied as gene therapy vectors and most have a deletion of the E3 region to permit the insertion of larger fragments of foreign DNA. Our results suggest that construction of Ad vectors to include E3 expression cassettes will improve the efficacy and safety of such viral-based gene therapy protocols

Maintenance therapy and need for cessation studies in multiple myeloma: Focus on the future

With ten years of follow-up since the advent of the modern paradigm of combination induction therapy, consolidative autologous stem-cell transplant, and lenalidomide maintenance, median survival for multiple myeloma has increased to almost 50% at 10 years. Given this outlook, the overarching goal of maintenance therapy is to spare patients from the toxicities of aggressive or otherwise intrusive therapies while ideally extending survival or, at the least, extending progression-free survival or time until next treatment. This review will focus on the current landscape of maintenance therapies for multiple myeloma. The historical context and evidence for choice of agent, duration of treatment, and current strategies and ongoing trials will be discussed - as well as a focus on unmet needs. The case for studies investigating cessation of therapy and risk and response-adapted approaches will be underscored given that the current paradigm likely results in overtreatment for some patients

Significant Nationwide Variability in the Costs and Hospital Mortality Rates of Autologous Stem Cell Transplantation for Multiple Myeloma: An Analysis of the Nationwide Inpatient Sample Database

•Nationwide disparities exist in inpatient care for recipients of autologous hematopoietic stem cell transplantation (AHCT) performed to treat multiple myeloma.•The low-volume centers (<3 annual unweighted AHCTs) have higher mortality.•Patients admitted to private hospitals have lower costs and mortality.•Further study should be done to adjust for myeloma-specific factors. Autologous hematopoietic stem cell transplantation (AHCT) is the standard of care for eligible patients with multiple myeloma (MM). In this study, we explored disparities in hospital cost and in-hospital mortality among patients with MM who underwent AHCT. Data were obtained from the Nationwide Inpatient Sample database for 2005 to 2014. International Classification of Diseases, Ninth Edition, Clinical Modification diagnosis and procedure codes were used to identify patients. Hospitals were divided into quintiles according to the weighted volume of AHCTs performed in patients with MM. Multiple imputation with chained equation was used for missing data. Linear trend analysis of age- and sex-adjusted mortality, as well as inflation-adjusted hospital cost, was performed. Univariate regression screening followed by stepwise multivariate regression was performed for dependent variables, including mortality and inflation-adjusted hospital cost. Identified significant predictors underwent sensitivity analyses. Overall age- and sex-adjusted mortality rates and inflation-adjusted hospital costs decreased between 2005 and 2014; however, tremendous nationwide variability exists. Patients who underwent AHCT at very-low-volume hospitals (Q1) had significantly higher in-hospital mortality. Both geographic location and hospital type had impacted age- and sex-adjusted mortality rates and inflation-adjusted hospital costs. Despite an overall improvement in mortality and decreased cost of AHCT for patients with MM, nationwide variability in care exists. Further study is needed to identify correctable factors that contribute to the identified correlation