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With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14 + cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin's lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3 + T cells. We demonstrated that monocyte depletion via rapid plastic surface adhesion significantly reduces the CD14 + monocyte content in the apheresis products and simultaneously boosts the CD3 + content. We established a 40% CD14 + threshold for the stratification of apheresis products across nine clinical trials and demonstrated the effectiveness of this procedure by comparing manufacturing runs in two phase 1 clinical trials. Our study suggests that CD14 + content should be monitored in apheresis products, and that the manufacturing of CAR T cells should incorporate a step that lessens the CD14 + cell content in apheresis products containing more than 40% to maximize the production success., Competing Interests: P.S.A. has received research funding from ATARA Biotherapeutics; has served on the Scientific Advisory Board or as consultant to ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, and Takeda Therapeutics; and has patents, royalties, and intellectual property on mesothelin-targeted CARs and other T cell therapies, method for detection of cancer cells using virus, and pending patent applications on T cell therapies. E.L.S. has patents, royalties, and intellectual property on BCMA-targeted CARs and serves as consultant for BMS. I.R. has intellectual property rights from Juno Therapeutics., (© 2021.)

Background: Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on safety and efficacy of autologous CD19-targeted CAR T-cells for these patients; here we report safety and long-term follow-up of CAR T-cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B-cell non-Hodgkin lymphoma (B-NHL)., Methods: We conducted a phase 1 clinical trial investigating CD19-targeted CAR T-cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of 20 patients received conditioning chemotherapy prior to CAR T-cell infusion. Five patients with CLL received ibrutinib at the time of autologous T-cell collection and/or CAR T-cell administration., Results: This analysis included 16 patients with R/R CLL and 4 patients with R/R indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients but grades 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T-cells and proportions of CD4+/CD8+ CAR T-cells with CD62L+CD127+ immunophenotype were significantly greater in patients on ibrutinib at leukapheresis. Three of 12 evaluable CLL patients receiving conditioning chemotherapy achieved CR (two had minimal residual disease-negative CR). All patients achieving CR remained progression-free at median follow-up of 53 months., Conclusion: Conditioning chemotherapy and 19-28z CAR T-cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with R/R CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. Ibrutinib therapy may modulate autologous T-cell phenotype., Trial Registration: ClinicalTrials.gov NCT00466531., Funding: Juno Therapeutics.

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m 2 ), followed by escalating doses of 3 × 10 6 , 1 × 10 7 , or 3 × 10 7 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation., (Copyright © 2018. Published by Elsevier Inc.)

Background: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients., Methods: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics., Results: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden., Conclusions: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

Originally implicated in axon guidance, semaphorins represent a large family of molecules that are now known to be expressed in the immune system. Among different semaphorins tested by reverse transcriptase-polymerase chain reaction in human immune cells, the expression of class 6 transmembrane semaphorin SEMA6A was restricted to dendritic cells (DCs). Using in-house generated monoclonal antibodies, SEMA6A expression appeared further restricted to Langerhans cells (LCs). In vivo, SEMA6A mRNA was expressed in freshly isolated skin LCs but SEMA6A protein was not detectable on normal skin and tonsillar epithelium. Of interest, SEMA6A protein was strongly expressed on skin and bone LCs and on LCs in draining lymph nodes from patients with LC histiocytosis or dermatopathic lymphadenitis, respectively, representing two inflammatory conditions in which LCs display an immature DC-LAMP(low), CD83(low), and CCR7+ phenotype. SEMA6A expression was low in resting LCs generated in vitro and was enhanced by interferon (IFN)-gamma but not by interleukin-4, interleukin-10, IFN-alpha/beta, or lipopolysaccharide. Most IFN-gamma-induced SEMA6A-positive cells remained immature with low CD83 and DC-LAMP/CD208 expression, but they expressed CCR7 and responded to macrophage inflammatory protein-3beta (MIP-3beta/CCL19). The expression of SEMA6A, for which the ligand and function remain unknown, may therefore identify an alternative IFN-gamma-dependent activation status of LCs in vivo.

We have studied the mechanisms by which human cytomegalovirus (HCMV) infection of monocyte-derived dendritic cells (moDCs) contribute to immune suppression. Unlike infection of immature moDCs, infection of mature moDCs is not lytic and results in minimally decreased surface major histocompatibility complex (MHC) and costimulatory molecule expression. The presence of a small percentage of CMV-infected mature moDCs, or the transfer of supernatant from infected moDCs depleted of infectious virions, is nevertheless sufficient to cause marked inhibition of immunostimulation by normal uninfected moDCs. Neither viral nor human interleukin 10 (IL-10) nor transforming growth factor-beta-1 (TGF-beta-1) could account for this inhibition. In contrast, we show that infected mature moDCs lose surface CD83 while maintaining intracellular protein expression. Soluble CD83 accumulates in the supernatants of CMV-infected mature moDCs, and CD83 immunodepletion removes the inhibitory effect of these supernatants on normal DC immunostimulation. We have thus discovered a new mechanism by which HCMV infection may establish a nonlytic reservoir in mature moDCs that inhibits DC-mediated T-cell responses.

Objective: To study the safety of discontinuing cytomegalovirus (CMV) maintenance therapy among patients with cured CMV retinitis receiving highly active antiretroviral therapy (HAART)., Methods: Patients with a history of CMV retinitis who were receiving anti-CMV maintenance therapy and who had a CD4 cell count > 75 x 10(6) cells/l and a plasma HIV RNA level < 30000 copies/ml while on HAART were included in a multicentre prospective study. Maintenance therapy for CMV retinitis was discontinued at enrolment and all the patients were monitored for 48 weeks by ophthalmological examinations and by determination of CMV markers, CD4 cell counts and plasma HIV RNA levels. T helper-1 anti-CMV responses were assessed in a subgroup of patients. The primary study endpoint was recurrence of CMV disease., Results: At entry, the 48 assessable patients had been taking HAART for a median of 18 months. The median CD4 cell count was 239 x 10(6) cells/l and the median HIV RNA load was 213 copies/ml. Over the 48 weeks, 2 of the 48 patients had a recurrence of CMV disease. The cumulative probability of CMV retinitis relapse was 2.2% at week 48 (95% confidence interval, 0.4-11.3) and that of all forms of CMV disease 4.2%. CMV blood markers remained negative throughout follow-up. The proportion of patients with CMV-specific CD4 T cell reactivity was 46% at baseline and 64% at week 48., Conclusions: CMV retinitis maintenance therapy may be safely discontinued in patients with CD4 cell counts above 75 x 10(6) cells/l who have been taking HAART for at least 18 months.

The classical refusal to perform rhinoplasty in elderly subjects needs to be revised. In fact, this operation gives satisfactory results provided the patients are well selected on the basis of psychological and anatomical criteria. Apart from the repair of accidental or surgical skin defects, the delayed request from rhinoplasty candidates should be carefully assessed and, when in doubt, the patient may require psychiatric consultation. The major technical problem is that of the lack of elasticity of the skin requiring very moderate modifications of the osteocartilaginous skeleton in every case and occasionally skin resections to allow skin cover of the revised structures. Various techniques for the root of the nose have been proposed. The classical difficulty for elderly people to assume their new body image is more theoretical than real provided "minimal" rhinoplasties are performed. This operation warrants a place in the surgery of ageing.

The term of "lethal midline granuloma" has been used to apply to a number of diseases. In this paper, it is argued that this term should be only a clinical description of a relentlessly progressive destructive lesion of the nose and face. A list of all the possible causes is presented. There is a group of patients who do not correspond to any specific etiology. Reviewing the observations in the literature and our own, we think that such cases are best classified according to their histological appearance. Those without atypical cells (20% of cases) are always localized to the upper respiratory tract, while those with atypical cells (histiocytes?), 80% of cases, may become generalized and/or may evolve to a malignant lymphoma. When localized, both forms (with and without atypical cells) respond very well to high-dose radiation therapy (40 to 60 Gy). In disseminated forms or relapses following radiotherapy treatment, chemotherapy, the only available alternative treatment, has met with little success. We present the clinical and pathological features of six such patients, of whom one had no atypical cells. Radiotherapy produced a clinical remission in five of five cases, but of shorter duration than that reported in the literature. No treatment other than radiotherapy has yet proven to be regularly efficient in this rare and mutilating disease.

A case of mycosis fungoides initiating in the cavum is reported. Results of biopsy of specimens taken from this region were negative, and diagnosis was established only after the appearance of lymph node and cutaneous lesions. The etiology is discussed, particularly in relation to the possible viral nature of the acquired immunodeficiency sundromes and more especially the "gay syndrome".

Hematoma and infection are particularly serious true complications of otoplasty because of the fragile nature of the cartilage. Perichondritis and chondritis are happily extremely rare sequelae as they may provoke veritable disasters. In contrast, imperfect results due to poor evaluation of protrusion factors or an unadapted technique are encountered less rarely. Schematically they can be divided into anomalies of the external ear in relation to the skull and morphological alterations. The former include overcorrections, or more usually insufficient corrections which may be uni or bilateral, global, or sectorial, particularly affecting the lobe. Among the latter are found poor reconstructions of the anthelix, which constitutes one of the most important elevations on the external ear, but also of the concha or helix. Corrective treatment consists mainly of procedures that were omitted or poorly performed during initial operations. Repeat surgery is always a delicate procedure, and the comments in this report should contribute to avoiding its necessity in the majority of cases.

Before a brief historical review of the disease, including its classical diagnostic criteria, the authors present a true case of Riedel's thyroiditis. After an initial operation involving virtually complete excision of the affected lobe, the course was particularly rapid with very extensive cervical fibrosis which resulted in death from tracheal and oesophageal complications. Such rapidly progressive secondary fibrosis has not been described before and did not have the histological characteristics of a recurrence. The authors liken it to phenomena of fibrosis frequently described as being associated with Riedel's disease (retroperitoneal fibrosis, fibrosing cholangitis, orbital pseudotumour, etc.). Bearing in mind that glucocorticosteroids have a beneficial action on such sites, the authors wonder whether routine preoperative corticosteroid therapy might not have avoided such an early fatal outcome in this patient.

Palliative surgery in patients with facial paralysis can be a useful temporary measure before nerve recuperation occurs, or a definitive procedure in cases with permanent loss of the effector muscle. Valid results can be obtained in the periorbital region by performing an external blepharorraphy, together with various static or dynamic procedures for louvering of the upper eyelid. The fascia lata is usually employed to obtain suspension, reequilibrium of soft tissues being ensared by lifting and localized cutaneous resections. Marked hyperactivity on the apposing side can be reduced by selective neurectomies.

The correction of nasal malformations in children divides surgeons into two groups: those who prefer to operate in order to rapidly restore the altered anatomical structures, and those who prefer to wait and see, to avoid aggravating the initial lesions by operating during the growth period. Clinical findings and animal experiments fail to clearly support either one of these approaches, at least in the case of very young children, but as recent embryological studies have demonstrated the important role of the septum in the growth of the nose, it still seems legitimate to recommend great caution before performing rhinoplasty in children: caution concerning the indications which should take into account major functional problems, caution in deciding the time of operation, which can frequently be delayed, caution in the technique which should be ultraconservative with preservation of the mucoperichondrium, reposition of the displaced fragments and reinclusion in the case of resection, caution in the desired goal of the operation as it is better to obtain a partial result with the possibility of subsequent revision rather than risk serious problems of growth. Rhinoplasty in young children is always difficult and should therefore remain an exceptional procedure.

After having emphasized the frequency of the newborn's and young child's nasal fractures, the authors insist on the difficulty of: - a precise outcome of the lesions, - the complications due to nasal obstruction, - the impossibility to anticipate the evolution of these lesions, which is being precised by a brief embryological recall. The traumas are deliberately presented according to the age of the patients: 1) the newborn's fractures: - the prenatal fractures, which generally have a favorable evolution. - obstetrical traumas, with nasal obstruction and feeding difficulty, both being indications to surgery. 2) The young child's fractures: often misknown, and relatively frequent, the nasal wall's hematoma is a dreadful complication. 3) During school years: (sports, car accidents, Silverman's syndrome) Nasal fractures are here generally associated to other facial lesions. Indications to surgery: Always: If it is a recent fracture, provoquing nasal obstruction with respiratory and feeding problems. Sometimes: Septoplasty as minima in case of respiratory difficulties. Never perform true rhinoplasty and/or osteotomies.

Confronted with nose malformations in children, surgeons experience at the same time a legitimate desire to rapidly attend to the altered anatomical structures, and a fear to aggravate the lesions existing initially by operating during a period of growth. Numerous animal experiments have not been conclusive as far as these two contradictory theses are concerned. In all cases, prudence remains mandatory, that is prudence towards the operational indications (important functional impairment), the date of the intervention (risk minimization with age), assessment of expected results (secondary malformations occurring even very late postoperatively).