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This article discusses the efficacy of a second round of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with diffuse large B-cell lymphoma (DLBCL) who did not respond to the initial treatment. The article highlights the limited treatment options for patients who do not respond to CAR T-cell therapy and presents data from various studies on the efficacy of a second infusion of CAR T-cells. The case study presented in the article demonstrates the potential for a second round of CAR T-cell therapy to achieve a prolonged complete response and the importance of considering a second infusion when B-cells reappear. The article emphasizes the need for further research on the benefits of CAR T-cell reinfusion after initial treatment failure. [Extracted from the article]

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Interestingly, CAR T cells were no longer detectable by flow cytometry at day+20 after axi-cel infusion in one of the responding patients, but we observed a new expansion of CD4+ and CD8+ CAR T cells after one dose of nivolumab (at day 144 after CAR T-cell infusion). Chimeric antigen receptor-engineered (CAR) T cells have demonstrated their efficacy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but still fail to induce a durable complete remission (CR) for most patients.[[1]] One potential mechanism of immune escape is the exhaustion of CAR T cells induced by the immunosuppressive tumour microenvironment.[[3]] The PD1/PD-L1 immune checkpoint pathway is strongly associated with CAR T-cell exhaustion.[5] The use of anti-PD1 inhibitor could generate a new CAR T-cell expansion and may improve the response.[6] We here report on 11 patients with R/R DLBCL who did not achieve CR after CD19 directed CAR T-cell therapy by axicabtagene ciloleucel (axi-cel) and who were treated subsequently with anti-PD1 nivolumab (240 mg/m SP 2 sp every 2 weeks) between 2019 and 2020. Safety and efficacy of nivolumab in patients who failed to achieve a complete remission after CD19-directed CAR T-cell therapy in diffuse large B cell lymphoma. [Extracted from the article]

Long-term care facility (LTCF) older residents display physiological alterations of cellular and humoral immunity that affect vaccine responses. Preliminary reports suggested a low early postvaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to focus on the specific T-cell response. We quantified S1-specific IgG, neutralizing antibody titers, total specific IFNγ-secreting T cells by ELISpot, and functionality of CD4+- and CD8+-specific T cells by flow cytometry, after two doses of the BNT162b2 vaccine in younger and older people, with and without previous COVID-19 infection (hereafter referred to as COVID-19-recovered and COVID-19-naive subjects, respectively). Frailty, nutritional, and immunosenescence parameters were collected at baseline in COVID-19-naive older people. We analyzed the immune response in 129 young adults (median age 44.0 years) and 105 older residents living in a LCTF (median age 86.5 years), 3 months after the first injection. Humoral and cellular memory responses were dramatically impaired in the COVID-19-naive older (n = 54) compared with the COVID-19-naive younger adults (n = 121). Notably, older participants' neutralizing antibodies were 10 times lower than the younger's antibody titers (p < 0.0001) and LCTF residents also had an impaired functional T-cell response: the frequencies of IFNγ+ and IFNγ+IL-2+TNFα+ cells among specific CD4+ T cells, and the frequency of specific CD8+ T cells were lower in COVID-19-naive older participants than in COVID-19-naive young adults (p < 0.0001 and p = 0.0018, respectively). However, COVID-19-recovered older participants (n = 51) had greater antibody and T-cell responses, including IFNγ+ and IFNγ+IL-2+TNFα+-specific CD4+ T cells (p < 0.0001), as well as TNFα+-specific CD8+ T cells (p < 0.001), than COVID-19-naive older adults. We also observed that "inflammageing" and particularly high plasma levels of TNFα was associated to poor antibody response in the older participants. In conclusion, our results show that the COVID-19-naive older people had low counts and impaired specific CD4+ and CD8+ T cells, in addition to impaired antibody response, and that specific studies are warranted to assess the efficiency of SARS-CoV-2 mRNA-based vaccines, as in other immunocompromised subjects. Our study also shows that, despite their physiological alterations of immunity, vaccination is highly efficient in boosting the prior natural memory response in COVID-19-recovered older people. [ABSTRACT FROM AUTHOR]

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial for studying long‐term immunity and vaccine strategies. We quantified IFNγ‐secreting T cells reactive against the main viral SARS‐CoV‐2 antigens using a standardised enzyme‐linked immunospot assay (ELISpot). Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T‐CoV‐Spot assay, we assessed T‐cell and antibody responses in mild, moderate and severe SARS‐CoV‐2 patients and in control samples collected before the outbreak. Results: Specific T cells were assessed in 60 consecutive patients (mild, n = 26; moderate, n = 10; and severe patients, n = 24) during their follow‐up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n = 60 (100%), n = 56 (93.3%), n = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T‐CoV‐Spot assay showed a specificity of 96.7% (95% CI, 88.5–99.6%) and a specificity of 90.3% (75.2–98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti‐S1 and anti‐RBD serum antibodies. Conclusion: IFNγ T‐CoV‐Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long‐lived memory T‐cell response after vaccination. Our study demonstrates that SARS‐CoV‐2 patients developing a severe disease achieve a higher adaptive immune response. [ABSTRACT FROM AUTHOR]

We investigated serum neutralizing activity against BA.1 and BA.2 Omicron sublineages and T cell response before and 3 months after administration of the booster vaccine in healthcare workers (HCWs). HCWs aged 18–65 years who were vaccinated and received booster doses of the BNT162b2 vaccine were included. Anti–SARS coronavirus 2 IgG levels and cellular response (through interferon γ ELISpot assay) were evaluated in all participants, and neutralizing antibodies against Delta, BA.1, and BA.2 were evaluated in participants with at least one follow-up visit 1 or 3 months after the administration of the booster dose. Among 118 HCWs who received the booster dose, 102 and 84 participants attended the 1-month and 3-month visits, respectively. Before the booster vaccine dose, a low serum neutralizing activity against Delta, BA.1, and BA.2 was detectable in only 39/102 (38.2%), 8/102 (7.8%), and 12/102 (11.8%) participants, respectively. At 3 months, neutralizing antibodies against Delta, BA.1, and BA.2 were detected in 84/84 (100%), 79/84 (94%), and 77/84 (92%) participants, respectively. Geometric mean titres of neutralizing antibodies against BA.1 and BA.2 were 2.2-fold and 2.8-fold reduced compared with those for Delta. From 1 to 3 months after the administration of the booster dose, participants with a recent history of SARS coronavirus 2 infection (n = 21/84) had persistent levels of S1 reactive specific T cells and neutralizing antibodies against Delta and BA.2 and 2.2-fold increase in neutralizing antibodies against BA.1 (p 0.014). Conversely, neutralizing antibody titres against Delta (2.5-fold decrease, p < 0.0001), BA.1 (1.5-fold, p 0.02), and BA.2 (2-fold, p < 0.0001) declined from 1 to 3 months after the administration of the booster dose in individuals without any recent infection. The booster vaccine dose provided significant and similar response against BA.1 and BA.2 Omicron sublineages; however, the immune response declined in the absence of recent infection. [ABSTRACT FROM AUTHOR]

The event of anti-CD19 chimeric antigen receptor (CAR)-T therapy inducing serious neurotoxicity in patients with diffuse large B-cell lymphoma (DLBCL) is recognized; however, the patterns of symptoms and severity vary greatly from patient to patient. We report an exceptional presentation of acute myelopathy in a refractory DLBCL following successful CAR-T treatment along with grade 3 cytokine release syndrome (CRS) and neurotoxicity. The patient was initiated on high-dose methylprednisolone (MPS) resulting in rapid improvement of neurological symptoms. Yet the myelopathy patient (MP) experienced severe lower limb motor deficit, and a subsequent spinal cord MRI revealed myelopathy with a sensory level at segment T2. Multimodal therapy consisting of MPS, intravenous immunoglobulin and anakinra therapy resulted in complete reversal of myelopathy condition and the patient remained cancer free. The assessment of time trends of serum cytokines at baseline and post CAR-T infusion in MP compared to other 4 DLBCL complete responder patients with varying degree of CRS following CAR-T infusion, suggested pre-existing baseline inflammatory conditions in MP with altered levels of cytokines. These findings, if corroborated by similar case studies, have the potential to generate novel insights into the manifestation of myelopathy following CAR-T therapy and the successful clinical management of such complications. [ABSTRACT FROM AUTHOR]

Aims: We investigated the relationships between control of glycemia and the frequencies of immune cell subpopulations and also the profile of circulating T cell cytokines in insulin-treated persons with type 1 diabetes (T1D).Methods: Clinical data and blood samples were collected from two groups of persons with T1D exhibiting either adequate (AGC) or inadequate glycemic control (IGC), as well as from individuals without diabetes considered as a control group. Serum cytokine levels and immune cell subpopulation frequencies were determined.Results: Irrespective of their capacity to control glycemia, the percentages of effector CD4+ T-cells and CD19+ B-cells were higher in persons with T1D than in controls, whilst monocytes were significantly more frequent in those with IGC than in controls. The overall frequencies of CD4+ T-cells, CD8+ T-cells and Foxp3+CD4+CD25+ regulatory T-cells did not differ between the three groups. The serum levels of IL-2 and IFN-γ were lower in both groups with T1D compared to controls, whilst the level of IL-4 did not differ. The level of IL-10 was significantly lower in those with AGC compared to controls.Conclusion: Our study shows that insulin treatment is associated with a Th2-biased systemic immune phenotype in persons with T1D, reflected by a high proportion of effector CD4+ T cells and CD19+ B cells and a down-regulation of Th1-type serum cytokines. [ABSTRACT FROM AUTHOR]