Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells.

BACKGROUND: The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. METHODS: The 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 GD2BATs/kg/infusion. RESULTS: Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. CONCLUSIONS: This study demonstrated the safety of GD2BATs up to 160×106 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

PURPOSE: The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy. METHODS: This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ. RESULTS: The highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009). CONCLUSION: Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM. CLINICALTRIALS: gov Identifier: NCT03344250.

Targeting GD2-positive Refractory/Resistant Neuroblastoma and Osteosarcoma with Anti- CD3 x Anti-GD2 Bispecific Antibody Armed T cells.

Background: Since treatment of neuroblastoma (NB) with anti-GD2 monoclonal antibodies provides a survival benefit in children with minimal residual disease and our preclinical study shows that anti-CD3 x anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs) were highly cytotoxic to GD2+ cell lines, we conducted a phase I/II study in recurrent/refractory patients to establish safety and explore the clinical benefit of GD2BATs. Methods: The 3+3 dose escalation study (NCT02173093) phase I involved 9 evaluable patients with NB (n=5), osteosarcoma (OST) (n=3), and desmoplastic small round cell tumors (DSRCT) (n=1) with twice weekly infusions of GD2BATs at 40, 80, or 160 x 106 GD2BATs/kg/infusion with daily interleukin 2 (300,000 IU/m2) and twice weekly granulocyte-macrophage colony stimulating factor (250 µg/m2). Phase II portion of the trial was conducted in patients with NB at the dose 3 level of 160 x 106 GD2BATs/kg/infusion but failed to enroll the planned number of patients. Results: Nine of 12 patients in the phase I completed therapy. There were no dose limiting toxicities (DLTs). All patients developed mild and manageable cytokine release syndrome (CRS) with grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody associated pain was not significant in this study. The median OS for patients in the Phase I and limited Phase II was 18.0 and 31.2 months, respectively, whereas the combined OS was 21.1 months. There was a complete bone marrow response with overall stable disease in one of the phase I patients with NB. Ten of 12 phase II patients were evaluable for response: 1 had partial response. Three additional patients were deemed to have clinical benefit with prolonged stable disease. More than 50% of evaluable patients showed augmented immune responses to GD2+ targets after GD2BATs as measured by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines. Conclusions: Our study demonstrated safety of up to 160 x 106 cells/kg/infusion of GD2BATs. Combined with evidence for the development of post treatment endogenous immune responses, this data supports further investigation of GD2 BATs in larger Phase II clinical trials.

Novel anti-CD30/CD3 bispecific antibodies activate human T cells and mediate potent anti-tumor activity.

CD30 is expressed on Hodgkin lymphomas (HL), many non-Hodgkin lymphomas (NHLs), and non-lymphoid malignancies in children and adults. Tumor expression, combined with restricted expression in healthy tissues, identifies CD30 as a promising immunotherapy target. An anti-CD30 antibody-drug conjugate (ADC) has been approved by the FDA for HL. While anti-CD30 ADCs and chimeric antigen receptors (CARs) have shown promise, their shortcomings and toxicities suggest that alternative treatments are needed. We developed novel anti-CD30 x anti-CD3 bispecific antibodies (biAbs) to coat activated patient T cells (ATCs) ex vivo prior to autologous re-infusions. Our goal is to harness the dual specificity of the biAb, the power of cellular therapy, and the safety of non-genetically modified autologous T cell infusions. We present a comprehensive characterization of the CD30 binding and tumor cell killing properties of these biAbs. Five unique murine monoclonal antibodies (mAbs) were generated against the extracellular domain of human CD30. Resultant anti-CD30 mAbs were purified and screened for binding specificity, affinity, and epitope recognition. Two lead mAb candidates with unique sequences and CD30 binding clusters that differ from the ADC in clinical use were identified. These mAbs were chemically conjugated with OKT3 (an anti-CD3 mAb). ATCs were armed and evaluated in vitro for binding, cytokine production, and cytotoxicity against tumor lines and then in vivo for tumor cell killing. Our lead mAb was subcloned to make a Master Cell Bank (MCB) and screened for binding against a library of human cell surface proteins. Only huCD30 was bound. These studies support a clinical trial in development employing ex vivo-loading of autologous T cells with this novel biAb.

SARS-CoV-2 Infection in Children with Idiopathic Nephrotic Syndrome: A Multicentric Study.

A multicenter retrospective study was conducted to assess the clinical spectrum of 30 severe acute respiratory syndrome coronavirus (SARS-CoV-2)-positive children with idiopathic nephrotic syndrome. Difficult to treat nephrotic syndrome was found to be a high-risk group with a high incidence of acute kidney injury and mortality.

Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab. PATIENTS AND METHODS: Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free survival (PFS). Peripheral blood mononuclear cells were obtained by a single apheresis, shipped to University of Virginia, activated with OKT3 and expanded for 14 days in IL2, harvested, and armed with HER2Bi and cryopreserved. HER2 BATs were infused twice weekly for 4 weeks and pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 to 3 weeks prior to HER2 BATs infusion. RESULTS: Fourteen patients were enrolled with a median age of 69 (range 57-82 years) and median PSA of 143.4 (range 8.2-4210 ng/dL). Two patients had peritoneal metastases, 1 had lymph node (LN) only metastases and 11 had bone metastases of which 7 had bone and LN metastases. All were pretreated with androgen receptor axis targeted agents and 7 (50%) had prior docetaxel chemotherapy. The toxicities were grade1-2 infusion reactions with fever, chills, headaches, nausea and/or myalgias. Primary endpoint of 6 month PFS was achieved in 5 of 14 patients (38.5%; 95% confidence interval, 19.5%-76.5%). Median PFS was 5 months and median survival was 31.6 months. CONCLUSIONS: The safety and promising efficacy makes this combination worthy of future investigation in mCRPC.

Therapeutic potential of Pogostemon cablin herb: a comprehensive review.

Pogostemon cablin (Pogostemon patchouli or Patchouli) is known for its essential oil and is a popular medicinal herb in Indian Ayurveda and traditional Chinese medicine. This review covers patent articles on the P. cablin plant's therapeutic effects. The patent literature was collected using a thorough, comprehensive search on databases like Thomson Innovation, Espacenet, Patentscope, The Lens and Patent digital libraries of different Jurisdictions, including IPO, USPTO, CNIPA, inPASS, KIPO, JPO, etc. Despite the vast number of review articles on non-patent literature, none of the articles reviewed the patent literature. This current P. cablin literature analysis study will facilitate bridging the gap between further exploring the potential of this plant through novel investigations.

Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia.

The management of relapsed or refractory acute myeloid leukemia (AML) continues to be therapeutically challenging. Non-toxic immunotherapy approaches are needed to provide long-term anti-leukemic effects. The goal of this study was to determine whether activated T cells (ATCs) armed with bispecific antibodies (BiAbs) could target and lyse leukemic and leukemic stem cells (LSCs). Anti-CD3 × anti-CD123 BiAb (CD123Bi) and anti-CD3 × anti-CD33GO (gemtuzumab ozogamicin [GO]) BiAb (CD33GOBi) were used to arm ATCs to produce bispecific antibody armed activated T cells (designated CD123 BATs or CD33GO BATs) to target AML cell lines, peripheral blood mononuclear cells from AML patients, and in vivo treatment of AML in xenogeneic NSG mice engrafted with leukemic cells. BATs exhibited high levels of specific cytotoxicity directed at AML cell lines at low 1:1 or 1:2 effector-to-target (E:T) ratios and secrete Th1 cytokines upon target engagement. In vivo study in AML-engrafted NSG mice showed significantly prolonged survival in mice treated with CD33GO BATs (p < 0.0001) or CD123 BATs (p < 0.0089) compared to ATC-treated control mice. Patient samples containing leukemic blasts and LSCs when treated with CD33GO BATs or CD123 BATs for 18 h showed a significant reduction (50%-100%; p < 0.005) in blasts and 75%-100% reduction in LSCs (p < 0.005) in most cases compared to unarmed ATCs. This approach may provide a potent and non-toxic strategy to target AML blasts and LSCs and enhance chemo-responsiveness in older patients who are likely to develop recurrent diseases.

Review of 13carbon nuclear magnetic resonance characterizations of dimethyltin carboxylates.

Diorganotin carboxylates have received much interest in past decades due to their rich structural chemistry and wide range of applications in various fields. This review study provides an in-depth analysis of carbon NMR data of dimethyltin complexes. The absorptions shown by the carbonyl carbon, methyl groups attached to tin and the other carbons present in the complexes were presented in this study. The effects of nature and the number of substituents attached are also described in this report.

Monkeypox Disease Outbreak (2022): Epidemiology, Challenges, and the Way Forward.

The biggest-ever outbreak of monkeypox disease in non-endemic countries started in May, 2022. Though no monkeypox case has been reported from India, till mid-June, 2022, yet, considering the rate of spread to the non-endemic countries, there is an urgent need of better understanding of the monkeypox virus and disease epidemiology to help clinicians, public health specialists, and policymakers to be prepared for any eventuality. This review summarises the monkeypox disease epidemiology, clinical features, therapies, vaccines and outlines the measures for preparedness and response for a possible outbreak. The disease is known to cause severe outcome in children, pregnant women, and immunocompromised hosts and this group need to be given special attention. The monkeypox disease outbreak (2022) in non-endemic countries should be used as an opportunity by India and other low and middle income countries to strengthen public health surveillance and health system capacity for outbreak and epidemic preparedness and response.

An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy.

Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1-GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.

Convalescent Plasma for Preventing Critical Illness in COVID-19: a Phase 2 Trial and Immune Profile.

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring frequent adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting. We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28-day mortality or alter levels of specific antibody responses before and after CIP infusion. In a single-arm phase II study, patients >18 years-old with respiratory symptoms with confirmed COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 h of admission. Levels of SARS-CoV-2 detected by PCR in the respiratory tract and circulating anti-SARS-CoV-2 antibody titers were sequentially measured before and after CIP transfusion. Twenty-nine patients were transfused high titer CIP and 48 contemporaneous comparable controls were identified. All classes of antibodies to the three SARS-CoV-2 target proteins were significantly increased at days 7 and 14 post-transfusion compared with baseline (P < 0.01). Anti-nucleocapsid IgA levels were reduced at day 28, suggesting that the initial rise may have been due to the contribution of CIP. The groups were well-balanced, without statistically significant differences in demographics or co-morbidities or use of remdesivir or dexamethasone. In participants transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298). IMPORTANCE Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations. This study informs the optimal timing and potential population of use for CIP in COVID-19, particularly in settings without access to other interventions, or in planning for future coronavirus pandemics.

Novel PE and APC tandems: Additional near-infrared fluorochromes for use in spectral flow cytometry.

Recent advances in flow cytometry instrumentation and fluorochrome chemistries have greatly increased fluorescent conjugated antibody combinations that can be used reliably and easily in routine experiments. The Cytek Aurora flow cytometer was first released with three excitation lasers (405, 488, and 640 nm) and incorporated the latest Avalanche Photodiode (APD) technology, demonstrating significant improvement in sensitivity for fluorescent emission signals longer than 800 nm. However, there are limited commercially available fluorochromes capable of excitation with peak emission signals beyond 800 nm. To address this gap, we engineered six new fluorochromes: PE-750, PE-800, PE-830 for the 488 nm laser and APC-750, APC-800, APC-830 for the 640 nm laser. Utilizing the principal of fluorescence resonance energy transfer (FRET), these novel structures were created by covalently linking a protein donor dye with an organic small molecule acceptor dye. Additionally, each of these fluorochrome conjugates were shown to be compatible with fixation/permeabilization buffer reagents, and demonstrated acceptable brightness and stability when conjugated to antigen-specific monoclonal antibodies. These six novel fluorochrome reagents can increase the numbers of fluorochromes that can be used on a spectral flow cytometer.

LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer.

Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer. SIGNIFICANCE: Enhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for "cold" microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.

Bispecific Antibody Armed Metabolically Enhanced Headless CAR T Cells.

Adoptive T cell therapies for solid tumors is challenging. We generated metabolically enhanced co-activated-T cells by transducing intracellular co-stimulatory (41BB, ICOS or ICOS-27) and CD3ζ T cell receptor signaling domains followed by arming with bispecific antibodies (BiAbs) to produce armed "Headless CAR T cells" (hCART). Various hCART armed with BiAb directed at CD3ϵ and various tumor associated antigens were tested for: 1) specific cytotoxicity against solid tumors targets; 2) repeated and dual sequential cytotoxicity; 3) survival and cytotoxicity under in vitro hypoxic condition; and 4) cytokine secretion. The 41BBζ transduced hCART (hCART41BBζ) armed with HER2 BiAb (HER2 hCART41BBζ) or armed with EGFR BiAb (EGFR hCART41BBζ) killed multiple tumor lines significantly better than control T cells and secreted Th1 cytokines/chemokines upon tumor engagement at effector to target ratio (E:T) of 2:1 or 1:1. HER2 hCART serially killed tumor targets up to 14 days. Sequential targeting of EGFR or HER2 positive tumors with HER2 hCART41BBζ followed by EGFR hCART41BBζ showed significantly increased cytotoxicity compared single antigen targeting and continue to kill under in vitro hypoxic conditions. In summary, metabolically enhanced headless CAR T cells are effective serial killers of tumor targets, secrete cytokines and chemokines, and continue to kill under in vitro hypoxic condition.

Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness.

In this study, we investigated the ability of bispecific antibody armed activated T cells to target drug resistant pancreatic cancer cells and whether or not "priming" these resistant cancer cells with bispecific antibody armed activated T cells could enhance subsequent responsiveness to chemotherapeutic drugs. Chemotherapeutic responses for pancreatic cancer are either limited or the tumors develop resistance to chemotherapy regimens. The impetus for this study was the remarkable clinical response seen in our earlier phase I/II clinical trial: a pancreatic cancer patient with drug resistant tumors who showed progression of disease following three infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) was restarted on the initial low dose of 5-fluorouracil showed complete response, suggesting that BATs infusions may have sensitized patient's tumor for chemoresponsiveness. In the current study, we tested the hypothesis that BATs can sensitize tumors for chemoresponsiveness. Gemcitabine or cisplatin-resistant MiaPaCa-2 and L3.6 cell lines were effectively targeted by EGFR BATs. Priming of drug sensitive or resistant cells with EGFR BATs followed by retargeting with lower concentrations of 50% inhibitory concentration of gemcitabine or cisplatin showed enhanced cytotoxicity. Gemcitabine or cisplatin-resistant cell lines show an increased proportion of CD44+/CD24+/EpCAM+ cancer stem like cells as well as an increased number of ABC transporter ABCG2 positive cells compared to the parental cell lines. These data suggest that bispecific antibody armed activated T cells can target and kill chemo-resistant tumor cells and also markedly augment subsequent chemotherapeutic responsiveness, possibly by modulating the expression of ABC transporters.

Acute Kidney Injury in Hospitalized Children with COVID19.

BACKGROUND: Acute kidney injury (AKI) has been recognized as a significant risk factor for mortality among adults with severe acute respiratory syndrome coronavirus infection. AIM: The aim of this study is to assess the prevalence and risk factors for AKI and mortality in children with coronavirus disease 2019 (COVID19) from a resource-limited setting. METHODS: Cross-sectional analysis of laboratory confirmed COVID19 children admitted from 1 March to 30 November 2020 in a tertiary care hospital in New Delhi, India was done. Clinical features and associated comorbidities of COVID19 were noted. Baseline serum creatinine (height-independent Hoste's equation) and peak serum creatinine were used for staging of AKI by the 2012 Kidney Disease Improving Global Outcomes serum creatinine criteria. Univariate analysis and Kaplan-Meier survival analysis were used to compare the overall outcome in the AKI vs. the non-AKI group. RESULTS: A total of 64 810 children between 1 month and 18 years visited the hospital; 3412 were tested for suspected COVID19, 295 tested positive and 105 (54% boys) were hospitalized. Twenty-four hospitalized children (22.8%) developed AKI; 8 in Stage 1 (33.3%), 7 in Stage 2 (29.2%) and 9 in Stage 3 (37.5%) respectively. Overall, three patients received KRT. Highest reported mortality was (66.6%) in AKI Stage 3. Risk factors for AKI included associated sepsis (OR 95% CI, 1.22-9.43, p < 0.01), nephrotic syndrome (OR 95% CI, 1.13-115.5, p < 0.01), vasopressor support (OR 3.59, 95% CI, 1.37-9.40, p value< 0.007), shock at presentation (OR 2.98, 95% CI, 1.16-7.60, p value 0.01) and mechanical ventilation (OR 2.64, 95% CI, 1.04-6.71, p value< 0.03). Mortality (25.71%) was higher in the AKI group (OR 95% CI, 1.14-8.35, p < 0.023) with shock (OR 45.92; 95% CI, 3.44-612.0, p value <0.004) and ventilation (OR 46.24; 95% CI, 1.6-1333.0 p value< 0.02) as significant risk factors for mortality. CONCLUSION: AKI is an important modifiable risk factor for mortality in children with COVID19 in a resource-limited setting. Our study supports the strengthening of kidney replacement therapy and its timely initiation to reduce the progression of AKI and thus mortality in children.

Phase II clinical trial using anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0-2+) metastatic breast cancer.

BACKGROUND: Metastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may be effective against HER2-tumors. This phase II trial evaluates the efficacy and immune responses of HER2 BATs given to patients with metastatic HER2-estrogen and/or progesterone receptor positive (HR+) and triple negative breast cancer (TNBC) as immune consolidation after chemotherapy. The primary objective of this study was to increase the traditional median time to progression after failure of first-line therapy of 2-4 months with the secondary endpoints of increasing overall survival (OS) and immune responses. METHODS: HER2- metastatic breast cancer (MBC) patients received 3 weekly infusions of HER2 BATs and a boost after 12 weeks. RESULTS: This phase II study included 24 HER2-HR+ and 8 TNBC patients who received a mean of 3.75 and 2.4 lines of prior chemotherapy, respectively. Eight of 32 evaluable patients were stable at 4 months after the first infusion. There were no dose limiting toxicities. Tumor markers decreased in 13 of 23 (56.5%) patients who had tumor markers. The median OS was 13.1 (95% CI 8.6 to 17.4), 15.2 (95% CI 8.6 to 19.8), and 12.3 (95% CI 2.1 to 17.8) months for the entire group, HER2-HR+, and TNBC patients, respectively. Median OS for patients with chemotherapy-sensitive and chemotherapy-resistant disease after chemotherapy was 14.6 (9.6-21.8) and 8.6 (3.3-17.3) months, respectively. There were statistically significant increases in interferon-γ immunospots, Th1 cytokines, Th2 cytokines, and chemokines after HER2 BATs infusions. CONCLUSIONS: In heavily pretreated HER2-patients, immune consolidation with HER2 BATs after chemotherapy appears to increase the proportion of patients who were stable at 4 months and the median OS for both groups as well as increased adaptive and innate antitumor responses. Future studies combining HER2 BATs with checkpoint inhibitors or other immunomodulators may improve clinical outcomes.

Diet and Dialogue Skills: An Innovative Approach to Diet Demonstration by Medical Students of Lady Hardinge Medical College.

BACKGROUND: Nutrition' is a very essential component of undergraduate teaching in MBBS curriculum. In this age of growing diet-consciousness and fitness, skill development of medical graduates in designing healthy and culturally appropriate diet is imperative. OBJECTIVE: To demonstrate the effectiveness of Diet Demonstration Training technique in improving the knowledge about basic principles of nutrition in medical undergraduates. METHODOLOGY: A pilot pretest-posttest study was conducted among 16 undergraduate medical students participated in a pre-conference workshop. Steps of diet demonstration for Under-graduate students were performed and a pretest - posttest was conducted using a self designed self administered questionnaire. RESULTS: The mean marks received by the students were 8.69 & 10.31 out of 15 in the pretest & post-test respectively (p value <0.017). Overall 56.3% & 93.6% students performed well in pre-test and post-test respectively. CONCLUSION: There was significant improvement in nutrition education of participated undergraduates.