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Key Points Cancer immunotherapies have the potential to generate robust antitumour responses; this can be achieved through several methods, such as modulatory antibodies or adoptive cellular therapy Since 2010, clinical trials using different immunotherapeutic approaches to treat patients with several tumour types have yielded unprecedented results In contrast with therapies that act on the tumour itself, immunotherapy-dependent antitumour responses can be sustained after the treatment has finished The optimal efficacy of immunotherapy will likely be achieved with designs that include combinations of different immunotherapeutic approaches, or immunotherapy combined with other cancer treatments The aim of immunotherapy is to treat cancer by enabling the immune system to attack the tumour. In the past decade, remarkable results have been obtained in clinical trials with immunotherapy for patients with advanced-stage cancer. Two types of immunotherapy have been used in the majority of trials conducted in the past decade: immune cell-targeted antibody therapy and adoptive cellular therapy. Herein, the latest advances in both modalities are discussed, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended. In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

Waldenstrom’s Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88 -mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22 / CD9 -positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice. The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.

Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the “antigen dilemma”, the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy. Claudin 18.2 (CLDN18.2) has emerged as a target for gastrointestinal cancer, however, on-target/off-tumor toxicities have been also reported. Here, after reporting evidence of erosive gastritis in patients treated with CLDN18.2 targeted immunotherapies, the authors develop and characterize CLDN18.2 fully-human VH-only single domain CARs, showing that a lower affinity CAR mitigates on-target/off-tumor toxicity while preserving anti-tumor efficacy in gastric cancer models.

The genetic modification of autologous T cells with chimeric antigen receptors (CARs) represents a breakthrough for gene engineering as a cancer therapy for hematologic malignancies. By targeting the CD19 antigen, we have demonstrated robust and rapid anti-leukemia activity in patients with heavily pre-treated and chemotherapy-refractory B cell acute lymphoblastic leukemia (B-ALL). We demonstrated rapid induction of deep molecular remissions in adults, which has been recently confirmed in a case report involving a child with B-ALL. In contrast to the results when treating B-ALL, outcomes have been more modest in patients with chronic lymphocytic leukemia (CLL) or other non-hodgkin’s lymphoma (NHL). We review the clinical trial experience targeting B-ALL and CLL and speculate on the possible reasons for the different outcomes and propose potential optimization to CAR T cell therapy when targeting CLL or other indolent NHL. Lastly, we discuss the pre-clinical development and potential for clinical translation for using CAR T cells against multiple myeloma and acute myeloid leukemia. We highlight the potential risks and benefits by targeting these poor outcome hematologic malignancies.

Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term \"social allostasis.\" We postulate that maternal food insecurity induces a \"superorganism\" state through coordination of individual HPA axis response. Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our \"dyadic vulnerability\" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively \"advantaged\" dyads exhibited maternal cortisol increases in response to VFD exposure. In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a \"superorganism\" version of HPA axis homeostasis, provisionally termed \"social allostasis.\"

Early-Life Stress and the Development of Obesity and Insulin Resistance in Juvenile Bonnet Macaques Daniel Kaufman 1 2 , Mary Ann Banerji 2 3 , Igor Shorman 1 2 , Eric L.P. Smith 2 4 , Jeremy D. Coplan 2 4 , Leonard A. Rosenblum 2 4 and John G. Kral 1 2 1 Department of Surgery, State University of New York Downstate Medical Center, Brooklyn, New York 2 Primate Behavior Laboratory, State University of New York Downstate Medical Center, Brooklyn, New York 3 Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York 4 Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, New York Address correspondence and reprint requests to John G. Kral, MD, PhD, Department of Surgery, Box 40, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. E-mail: jkral{at}downstate.edu Abstract Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infant's growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance. CRF, corticotrophin-releasing factor CRL, crown-rump length csf, cerebrospinal fluid GLP-1, glucagon-like peptide-1 HFD, high foraging demand HOMA, homeostasis model assessment HPA, hypothalamo-pituitary-adrenal IGR, insulin-to-glucose ratio LFD, low foraging demand TG, triglyceride VFD, variable foraging demand Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 18, 2006. Received October 5, 2006. DIABETES

BackgroundWaldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM.Methods and resultsWe performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment.ConclusionsThis report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor (CAR) T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

The demand for revision total joint arthroplasties (rTJAs) is expected to increase as the age of the population continues to rise. Accurate cost data regarding hospital expenses for differing age groups are needed to deliver optimal care within value-based healthcare (VBHC) models. The aim of this study was to compare the total in-hospital costs by decadal groups following rTJA and to determine the primary drivers of the costs for these procedures. Time-driven activity-based costing (TDABC) was used to capture granular hospital costs. A total of 551 rTJAs were included in the study, with 294 sexagenarians, 198 septuagenarians, and 59 octogenarians and older. Sexagenarians had a lower ASA classification (2.3 vs. 2.4 and 2.7; p < 0.0001) and were more often privately insured (66.7% vs. 24.2% and 33.9%; p < 0.0001) as compared to septuagenarians and octogenarians and older, respectively. Sexagenarians were discharged to home at a higher rate (85.3% vs. 68.3% and 34.3%; p < 0.0001), experienced a longer operating room (OR) time (199.8 min vs. 189.7 min and 172.3 min; p = 0.0195), and had a differing overall hospital length of stay (2.8 days vs. 2.7 days and 3.6 days; p = 0.0086) compared to septuagenarians and octogenarians and older, respectively. Sexagenarians had 7% and 23% less expensive personnel costs from post-anesthesia care unit (PACU) to discharge (p < 0.0001), and 1% and 24% more expensive implant costs (p = 0.077) compared to septuagenarians and octogenarians and older, respectively. Sexagenarians had a lower total in-hospital cost for rTJAs by 0.9% compared to septuagenarians but 12% more expensive total in-hospital costs compared to octogenarians and older (p = 0.185). Multivariate linear regression showed that the implant cost (0.88389; p < 0.0001), OR time (0.12140; p < 0.0001), personnel cost from PACU through to discharge (0.11472; p = 0.0007), and rTHAs (−0.03058; p < 0.0001) to be the strongest associations with overall costs. Focusing on the implant costs and OR times to reduce costs for all age groups for rTJAs is important to provide cost-effective VBHC.