Intact Immunity Research Articles

Photogallery. Human papillomavirus infection of the skin and mucous membranes in people living with HIV

The human papillomavirus is ubiquitous. It is estimated that over a third of people with apparently healthy skin are carriers of human papillomavirus. HIV-associated immunodeficiency contributes to the manifestation of clinical symptoms of human papillomavirus infection. Against the background of severe (the number of CD4+ T-lymphocytes below 200 cells/μl) and pronounced (CD4+ T-lymphocytes from 200 to 349 cells/μl) immunodeficiency caused by HIV infection (human immunodeficiency virus), the period of persistence of human papillomavirus is longer, and the clinical picture and course of human papillomavirus infection can significantly differ compared to HIV-positive individuals with intact immunity and people without HIV. At the same time, formations on the skin and mucous membranes are often multiple and can be characterized by rapid growth, large size, location outside the typical localization, resistance to treatment, recurrent course, and lack of tendency to spontaneous regression. Taking antiretroviral drugs for the treatment of HIV infection has a generally beneficial effect on the clinical course and prognosis of viral warts; With regard to anogenital warts, the researchers’ conclusions are not so clear. A number of experts believe that viral-immunological control of HIV infection may not be sufficient to successfully combat venereal warts. The photogallery presents various clinical types of viral and anogenital (venereal) warts in people living with HIV. Each of them is assigned one of the variants of the stage of secondary diseases of HIV infection (4A, 4B or 4V according to its Russian clinical classification) depending on the severity of concomitant opportunistic diseases. In all clinical cases, with the exception of the last one, patients experienced severe or pronounced immunodeficiency and progression of HIV infection in the absence of antiretroviral therapy. In the last observation, giant Buschke–Levenstein condyloma developed with a slight immunodeficiency against the background of effective antiretroviral therapy.

Inhibitory Effect of Pyra-Metho-Carnil on the Differentiation and Maturation of Macrophages in Normal and Cancer Microenvironments.

In a previous study, we have demonstrated heightened Pyra-Metho-Carnil (PMC) efficacy in nude mice with intact innate immunity that lack T and B cells. This has prompted hypothesizing that PMC may target macrophages that promote cancer growth. In this study, we conducted co-culture experiments with macrophages derived from THP-1 human monocyte cell lines and spheroids representing normal and cancer microenvironments. We then performed RNA sequencing and flow cytometry analysis to elucidate the mechanisms by which PMC affects macrophage differentiation and maturation. THP-1 cells were differentiated by phorbol 12-myristate 13-acetate (PMA) and matured by PMA and lipopolysaccharide (LPS) either with or without PMC. Co-cultures were performed using stimulated THP-1 cells and HKe3-wild-type KRAS or HKe3-mutant (mt) KRAS spheroids. We then performed RNA-seq analysis of THP-1 cells stimulated by PMA (either with or without PMC) and flow cytometry analysis of mice peripheral blood obtained after PMC administration. THP-1 cells matured by PMA and LPS specifically increased the area of HKe3-mtKRAS cancer spheroids and the addition of PMC to THP-1 cells was found to inhibit cancer spheroid growth. RNA-seq data suggested that PMC treatment of THP-1 cells stimulated with PMA suppressed cell motility regulatory functions via down-regulation of the NF[Formula: see text]B pathway. Furthermore, flow cytometry results showed that PMC treatment suppressed monocyte maturation in B6 mice. The high level of in vivo tumor suppression caused by PMC may be due to inhibition of the differentiation and maturation of tumor-associated macrophages via the NF[Formula: see text]B signaling pathway.

A narrative review of the controversy on the risk of mycobacterial infections with immune checkpoint inhibitor use: does Goldilocks have the answer?

Immune checkpoint inhibitors (ICIs) have revolutionized oncologic treatment. Whether ICIs increase susceptibility to or provide protection against mycobacterial infections remains controversial. The objective of this narrative review is to summarize the literature on the link between ICI use and mycobacterial infections-tuberculosis and non-tuberculous mycobacterial (NTM) infections-and to critically discuss evidence linking ICIs with mycobacterial infections, the possible confounders, and, if indeed the ICIs predispose to such infections, the potential mechanisms of how this may occur. We conducted a literature search on PubMed for relevant articles published from 2011 to current time [2024] utilizing specific keywords of "immune checkpoint inhibitors", "programmed cell death protein-1", "PD-1", "programmed death-ligand 1", "PD-L1", "cytotoxic T-lymphocyte-associated protein-4", or "CTLA-4" with that of "non-tuberculous mycobacterial lung disease", "tuberculosis", or "mycobacteria". The bibliographies of identified papers were perused for additional relevant articles. Ex vivo studies using human cells indicate that ICIs would be salubrious for the host against mycobacteria. Yet, many case reports associate ICI use with mycobacterial infections, mostly tuberculosis. Potential confounders include immunosuppression from the cancer, concomitant use of immunosuppressive drugs, lung injury and distortion from chemotherapeutics or radiation, and reporting bias. Mice with genetic disruption of the programmed cell death protein-1 (PD-1) gene are paradoxically more susceptible to Mycobacterium tuberculosis (M. tuberculosis). In contrast, mice administered neutralizing antibody to T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) or knocked out for TIM3 gene have greater capacity to control an M. tuberculosis infection. We posit that hosts with greater baseline immunodeficiency are more likely to derive benefit from ICIs against mycobacterial infections than those with more intact immunity, where ICIs are more likely to be detrimental. Studies are needed to test the hypothesis that ICIs may either protect or predispose to mycobacterial infections, depending on the baseline host immune status. Prospective studies are required of patients on ICIs that control for potential confounders as anecdotal case reports are insufficient to provide a causal link. Murine studies with ICIs are also required to corroborate or refute studies of mice with genetic disruption of an immune checkpoint.

MRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell...

Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection

Crimean-Congo hemorrhagic fever virus (CCHFV) causes Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there is neither an approved antiviral drug nor a vaccine against CCHFV. In this study, we describe a lethal model of CCHFV infection using a mouse-adapted strain of CCHFV (MA-CCHFV) in adult wild-type male mice. Infected mice developed high viral loads, tissue pathology, and inflammatory immune responses before ultimately succumbing to the infection. We used the model to evaluate the protective efficacy of nucleoside analogs monulpiravir, favipiravir, ribavirin, the antibiotic tigecycline and the corticosteroids dexamethasone and methylprednisolone against lethal CCHFV infection. Tigecycline, monulpiravir and the corticosteroids failed to protect mice from lethal MA-CCHFV infection. In contrast, favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed. Despite demonstrating uniform protection, CCHFV RNA persisted in survivors treated with favipiravir and ribavirin. Nevertheless, the study demonstrated the anti-CCHFV efficacy of favipiravir and ribavirin in a model with intact innate immunity and establishes this model for continued development of CCHFV countermeasures.

Clinical and immunological characteristics for BK polyomavirus-associated nephropathy after kidney transplantation.

BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific immunity is associated with viral containment. This study investigated BKPyV-specific immunological factors among KT recipients. This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV-cell-specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon-gamma (IFN-γ)-producing CD4+ T, CD8+ T, natural killer (NK), and natural killerT (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1). In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1-year cumulative incidence of high-level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre-KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077-1.469; p = .004) and %VP1-specific NK cells (HR, 1.209; 95% CI, 1.055-1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1-specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05). Individuals with nonspecific and VP1-specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high-level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV-specific innate immune surveillance in predicting the occurrence of BKPyVAN.

Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors.

Human melanoma is the most aggressive form of skin cancer and is responsible for the most deaths of all skin cancers. Localized tumors, and those which have limited spread, have 5-year survival rates of over 90%, with those numbers steadily rising over the past decade. However, metastatic melanomas have a sharp decrease in 5-year survival rates and are still an area of need for new, successful therapies. Immuno-oncolytic viruses (OVs) have emerged as a promising class of immunovirotherapy that can potentially address this disease. The Food and Drug Administration in the United States has approved one oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene Laherparepvec) for the treatment of metastatic melanoma, and others could soon follow for this and other cancers. In previous studies, Tanapoxvirus (TPV) recombinants expressing mouse interleukin-2 (mIL-2) and another expressing bacterial flagellin from Salmonella typhimurium (FliC) have demonstrated anti-tumor efficacy in nude mouse models. TPV replicates only in humans and monkeys, including tumor cells, which makes the use of syngeneic tumor models impossible for the study of this OV in a standard immunocompetent system. In this study, TPV/Δ66R/mIL-2 and TPV/Δ2L/Δ66R/FliC were tested for their ability to treat human melanoma xenografts (SK-MEL3) in a BALB/c nude mouse model reconstituted with splenocytes from genetically compatible, normal BALB/c donor mice. Two SK-MEL3 tumors were transplanted into each flank of BALB/c nude mice, and the larger tumor was treated intratumorally (IT) with virus or mock injection. In one set of animals, mice received adoptive transfers of splenocytes from BALB/c mice on day 4 to reconstitute their immune systems and allow for adaptive immune responses to occur in a xenograft model. Direct IT injection of TPV/Δ66R/mIL-2 led to significantly greater rates of tumor regression compared to reconstituted control (RC) mice in the primary and distant tumor sites, whereas TPV/Δ2L/Δ66R/FliC treatment led to significantly greater rates of tumor regression in distant tumor sites only. A second experiment used TPV/Δ66R/mIL-2 to test whether TPV could be administered intravenously (IV), intramuscularly (IM), or both routes simultaneously to exert similar anti-tumor effects in an indirectly treated tumor. A single SK-MEL3 tumor was transplanted into one flank of BALB/c nude mice and was treated either into the tail vein, the nearest rear leg to the tumor, or both. All mice then received adoptive transfers of splenocytes in the same way as previously described on day 4 and received an additional TPV treatment on day 14. The results demonstrated that TPV/Δ66R/mIL-2 treatment IV or IM had significantly greater rates of tumor regression than RC-treated mice but failed to exert this effect when both routes were used simultaneously. Data obtained through these experiments support the continued development of Tanapoxvirus for the treatment of human melanoma and using immune reconstitution to create intact adaptive immunity in a xenograft context, which can allow other tropism-limited OVs to be studied against human cancers.

Outcome of short course chemotherapy of tuberculosis verrucosa cutis in a child

Abstract Tuberculosis verrucosa cutis (TBVC) is an exogenous form of cutaneous tuberculosis (TB) due to accidental inoculation of mycobacterium TB from tubercular material like sputum into the exposed areas of skin with the minor traumatic lesion of a previously infected individual with intact cell-mediated immunity. In India, TBVC often occurs in the lower extremities and involvement of the elbow is unusual. Excellent response to anti-TB treatment (ATT) is the characteristic feature of TBVC. A case of TBVC at the left elbow in a 10-year-old boy with partial resolution at the end of ATT is reported. Chronicity and the initial size of skin lesion may be one of the reasons for the incomplete resolution of TBVC even after short-course chemotherapy with daily isoniazid, rifampicin, ethambutol and pyrazinamide for the first 2 months followed by 4 months of daily isoniazid and rifampicin in some cases. Topical application of a keratolytic drug like 3% salicylic acid may be effective in further thinning of residual lesions of TBVC.

RARE CASE OF HOMOZYGOUS IFNAR1 DEFICIENCY IN A SAMOAN CHILD WITH DISSEMINATED VARICELLA AFTER VACCINATION

<h3>Introduction</h3> Autosomal recessive interferon alpha/beta receptor 1 (IFNAR1) deficiency increases susceptibility to live-attenuated vaccines and wild-type viruses. Currently 16 cases, half with Polynesian ancestry have been reported since the discovery in 2019. Most cases present with severe MMR or yellow fever vaccine-related disease. Some cases report severe SARS-CoV-2, herpes simplex, and enterovirus. Varicella vaccine-related disease has been hypothesized but not previously reported. <h3>Case Description</h3> A pediatric Samoan girl with congenital cardiac anomaly, otherwise healthy until receiving Varicella and MMR vaccines at 12 months. Two weeks later with presumed incomplete Kawasaki Disease with 10-day fever, red lips, and maculopapular rash, given IVIG and infliximab; also, positive SARS-CoV-2 PCR and IgG that admission. Developed diffuse vesicular rash 3 weeks after vaccination requiring re-admission for disseminated varicella. At 14 months, admitted again for acute respiratory failure with viral pericarditis, positive for rhinovirus/enterovirus on respiratory viral panel and varicella serum PCR. Samoan parents are first-degree cousins and her stillborn sister had significant homozygosity on genetic evaluation. Normal lymphocyte subsets, normal mitogen proliferation, absent antigen proliferation in vitro, and normal NK function. Intact humoral immunity. Primary immunodeficiency disease panel identified homozygous pathogenic variant in IFNAR1. Future live viral vaccines contraindicated. Managed with acyclovir with return to baseline. <h3>Discussion</h3> This case demonstrates a novel finding of homozygous IFNAR1 deficiency predisposing to disseminated varicella after vaccination. TNF inhibition may have also contributed. IFNAR1 deficiency should be considered in patients with severe varicella or other severe viral illnesses, especially after live-attenuated viral vaccines in those of Polynesian ancestry.

Recurrent Bacterial Meningitis Associated with Inflammatory Nasal Polyp

In case of no head trauma history and intact immunity, adultonset recurrent bacterial meningitis is scarce. Parameningeal infection is the crucial latent cause of recurrent bacterial meningitis in adults. Nasal polyp can cause a variety of nasal symptoms, depending on its location and size. Chronic sinusitis with nasal polyp tends to have more severe symptoms than those without nasal polyp. We report a case of adult onset third recurrent bacterial meningitis associated with inflammatory nasal polyp.

Abstract 2189: The role of generational obesity on the ovarian metastatic niche

Abstract Obesity is a worldwide epidemic associated with many cancer types due to persistent inflammation, hyperglycemia and hyperinsulinemia providing an abundance of nutrients and growth factors to cancer cells resulting in an ideal microenvironment. Maternal obesity often results in an increased risk of offspring developing obesity. Chronic inflammation and immunosuppression found in obese patients have been linked to ovarian cancer (OvCa). OvCa is the most lethal gynecological malignancy among women and approximately 12% of OvCa patients are obese. Poor survival rates are attributable to women presenting with advanced disease with disseminated intraperitoneal (i.p) metastasis at diagnosis. Metastatic tumor cells shed from the primary tumor and preferentially home to the mesothelium of the omentum and other peritoneal organs producing secondary lesions. Developmental programming suggests that perinatal nutritional influences can alter gene expression in offspring. A pre-clinical murine model of diet-induced obesity that included maternal cohorts of C57BL/6 mice (dam) with intact host immunity fed either a control diet (CD; 10% fat) or a high-fat diet (HFD; 40% fat) and the resulting offspring fed either diet was utilized to explore diet induced genetic and physical modifications. Body composition analysis revealed differences in weight and lean mass was dependent on offspring diet alone and fat mass was dam diet dependent among CD fed offspring. Second harmonic generation microscopy demonstrated a larger area of collagen mesh-work between fenestrations in the omentum of HFD fed mice as well as an increase in anisotropy. Additionally, a tumor study was performed using either CD or HFD fed offspring to quantify site-specific metastatic success to the adipose-rich tissues of the peritoneal cavity. Mice were injected i.p. with fluorescently tagged syngeneic ID8 murine OvCa cells and disease progression was tracked for 8 weeks. Abdominal organs were dissected, imaged, and organ-specific tumor burden quantified. Overall, offspring fed a HFD displayed an increase in organ-specific tumor burden relative to offspring fed a CD, regardless of dam diet. Furthermore, HFD offspring from HFD dams displayed higher omental tumor burden than HFD offspring from CD dams. In addition, HFD fed mice accumulated more ascites fluid than CD fed mice, however variances were independent of dam diet. Comparison of ascites cytokine expression revealed CXCL13, a dominant chemokine in adipocytes, was significantly increased in mice only exposed to a HFD suggesting an additive effect of both maternal and offspring obesity. Interestingly, increased CXCL13 expression has been reported in OvCa cell lines and in clinical samples. Together, the results suggest maternal obesity or subsequent exposure to a HFD can influence ovarian cancer metastasis. Citation Format: Tyvette Hilliard, Phillip Petrasko, Yueying Liu, Jing Yang, Marwa Asem, Jeff Johnson, Gifty Marfowaa, Brooke Kowalski, Elinor Schnautz, Morgan McCabe, M. Sharon Stack. The role of generational obesity on the ovarian metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2189.

Robust homotypic and heterosubytpic immunity against Influenza A Virus in mice lacking Th1/Tc1 transcriptional machinery

Abstract T cell responses against Influenza A Virus (IAV) are dominated by IFN-γ producing CD4 (Th1) and CD8 (Tc1) cells with little IL-17 production. However, loss of the transcription factors T-bet (Tbx21), the master Th1 regulator, and its paralog, Eomesodermin (Eomes), that influences both Th1 and Tc1 functionality, unleashes a strong Th17/Tc17 response while nearly eradicating IFN-γ production and other Th1/Tc1 hallmarks of antiviral T cells. Although Tbx21−/−Eomes−/− mice infected with LCMV were shown to succumb to Tc17 mediated wasting disease, we find that Tbx21−/−Eomes−/− mice survive primary H1N1 IAV infection and clear the virus with similar kinetics as do wild type (WT) mice. Long-lived IAV-specific IgG titers are also similar between Tbx21−/−Eomes−/− and WT mice, correlating with comparable follicular T helper cell responses. Furthermore, primed Tbx21−/−Eomes−/− mice maintain robust homotypic protection against supralethal H1N1 rechallenge indicating highly functional humoral immunity. Strikingly, H1N1-primed Tbx21−/−Eomes−/− mice also survive supralethal H3N2 IAV challenge, indicating intact heterosubtypic immunity as judged by similar viral control, weight loss kinetics and remarkably, no differences in immunopathology versus WT mice despite an overwhelming Th17/Tc17-biased inflammatory response. This cross-protection is T cell dependent as H1N1-primed Tbx21−/−Eomes−/− mice depleted of CD4 and CD8 T cells do not recover or control the H3N2 challenge virus. Our observations thus support that T-bet- and Eomes-independent effector T cells can provide robust long-term protection, potentially extending the available mechanisms for vaccines to target T cell-mediated immunity against IAV. Supported by grants from NIH (R21AI146647)

Abstract P1-08-11: Clinical relevance of host immunity in patients with breast cancer who received neoadjuvant chemotherapy

Abstract Background Host immunity plays a key role in breast cancer progression. It seems that the neutrophil-to-lymphocyte ratio (NLR) may reflect the systemic host immunity, and tumor-infiltrating lymphocytes (TILs) may reflect the localized host immunity. This study aimed to analyze the clinical relevance of host immunity combining NLR and TILs to treatment efficacy and survival.Methods We assessed the pre-treatment NLR and TILs from core-biopsy samples in 461 patients with breast cancer who received neoadjuvant chemotherapy. The patients were assigned into two groups: the intact host immunity group (NLR &amp;lt; 2.75 and TILs ≥ 30%) and the defective host immunity group (the remainder; NLR &amp;gt; 2.75 or TILs &amp;lt; 30%). We investigated the pathologic complete response (pCR) and recurrence-free survival (RFS) according to host immunity.ResultsOf the total, 141 (30.6%) patients belong to the intact host immunity group, and 320 (69.4%) patients belong to the defective host immunity group. A pCR was achieved in 76 (53.9%) of 141 patients in the intact host immunity group, whereas a pCR was achieved in 96 (30.0%) of 320 patients in the defective host immunity group (P&amp;lt;0.001). The intact host immunity was an independent predictor for high pCR (adjusted odds ratio [OR], 2.65; 95% confidence interval [CI], 1.74-4.03). Furthermore, the Cox proportional hazards regression models revealed that the intact host immunity obtained an independent prognostic value for favorable RFS after adjusted for clinicopathologic factors including pCR (adjusted hazard ratio [HR], 0.33; 95% CI, 0.11-0.98; P=0.045).ConclusionHost immunity based on the combined analysis of NLR and TILs provides information regarding the treatment response and prognosis in patients with breast cancer receiving neoadjuvant chemotherapy. There is a need for a new therapeutic strategy to activate the immune system in patients with defective host immunity. 2 Citation Format: Soong June Bae, Jung Hwan Ji, Chihhao Chu, Yoon Jin Cha, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. Clinical relevance of host immunity in patients with breast cancer who received neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-11.

Abstract P5-13-05: Multiplex spatial systems analysis of responses to spatially separate nanoliter doses of drug predicts systemic immune-modulating combination treatments in breast cancer

Abstract Most targeted and chemotherapeutic agents in use today affect both the tumor and the associated tumor microenvironment (TME) and should be combined to achieve effective control by simultaneously attacking tumor intrinsic vulnerabilities, enhancing immune surveillance, and mitigating stromal mediators of resistance. We have developed an integrated technological platform that enables rapid identification of such combinations by effective, fast and harmless assessment of TME responses to multiple drugs or drug combinations. This approach uses an implantable microdevice for delivery of dozens of treatments into spatially separated regions of a single living tumor and multiplexed histology analyses with probes for 30+ proteins to interrogate the responses of tumor epithelial cells, cancer associated fibroblasts, endothelial cells, lymphoid and myeloid immune lineages. Responses of interest include changes in differentiation state, antigenicity and immunogenic cell death. We demonstrated the utility of this platform by performing an unbiased in vivo screen to assess the effects of seven FDA approved drugs and combinations thereof on two late-stage mouse models of breast cancer with intact immunity. These studies indicated that the most effective, immunogenic, tumor cell kill was produced by the epigenetic modulator, panobinostat, and was linked with upregulation of MHC-I expression on tumor cells, and recruitment of antigen presenting macrophages and cytotoxic neutrophils. Increased expression of Galectin-3 and Neuropilin-1 on cancer stem cells and neutrophils, respectively, correlated with the therapeutic response three days after drug exposure, suggesting a functional role of these two proteins in early events of induced anti-tumor immunity. Our spatial systems analyses also revealed a key role for density of cancer stem cells (CSCs) and formation of fibroblasts/ECM barriers as potential resistance mechanisms. Addition of the BCL2 inhibitor, venetoclax, enhanced panobinostat anti-tumor activity, and the local phenotypic cell responses involving dendritic cell recruitment and clustering to CSC microculture suggested the use of anti-CD40 immunotherapy to induce maximum therapeutic effect. We demonstrated that a panobinostast-venetoclax-anti-CD40 therapeutic combination predicted from microdevice analyses was effective in whole animal studies in multiple models of breast cancer and often resulted in complete tumor control. Generalization of this approach promises to enable rapid design of personalized drug combination regimens that maximize tumor cell eradication by direct action on the tumor cells and by creating effective antitumor microenvironments. We demonstrated the utility of the approach in model systems but application in humans is now underway. Citation Format: Zuzana Tatarova, Dylan C Blumberg, Lisa M Coussens, Gordon B Mills, Oliver Jonas, Joe W Gray. Multiplex spatial systems analysis of responses to spatially separate nanoliter doses of drug predicts systemic immune-modulating combination treatments in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-05.

Immunity to Invasive Fungal Diseases.

Invasive fungal diseases are rare in individuals with intact immunity. This, together with the fact that there are only a few species that account for most mycotic diseases, implies a remarkable natural resistance to pathogenic fungi. Mammalian immunity to fungi rests on two pillars, powerful immune mechanisms and elevated temperatures that create a thermal restriction zone for most fungal species. Conditions associated with increased susceptibility generally reflect major disturbances of immune function involving both the cellular and humoral innate and adaptive arms, which implies considerable redundancy in host defense mechanisms against fungi. In general, tissue fungal invasion is controlled through either neutrophil or granulomatous inflammation, depending on the fungal species. Neutrophils are critical against Candida spp. and Aspergillus spp. while macrophages are essential for controlling mycoses due to Cryptococcus spp., Histoplasma spp., and other fungi. The increasing number of immunocompromised patients together with climate change could significantly increase the prevalence of fungal diseases.

Immunogenicity of an inactivated SARS-CoV-2 vaccine in people living with HIV-1: a non-randomized cohort study.

BackgroundInactivated COVID-19 vaccines are safe and effective in the general population with intact immunity. However, their safety and immunogenicity have not been demonstrated in people living with HIV (PLWH).Methods42 HIV-1 infected individuals who were stable on combination antiretroviral therapy (cART) and 28 healthy individuals were enrolled in this open-label two-arm non-randomized study at Hubei Provincial Center for Disease Control and Prevention, China. Two doses of an inactivated COVID-19 vaccine (BBIBP-CorV) were given on April 22, 2021 and May 25, 2021, respectively. The reactogenicity of the vaccine were evaluated by observing clinical adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and surrogate neutralization assays. Cell-mediated immune responses and vaccine induced T cell activation were measured by flow cytometry.FindingsAll the HIV-1 infected participants had a CD4+ T cell count >200 cells/μL both at baseline (659·0 ± 221·9 cells/μL) and 4 weeks after vaccination (476·9 ± 150·8 cells/μL). No solicited adverse reaction was observed among all participants. Similar binding antibody, neutralizing antibody and S protein specific T cell responses were elicited in PLWH and healthy individuals. PLWH with low baseline CD4+/CD8+ T cell ratios (<0·6) generated lower antibody responses after vaccination than PLWH with medium (0·6∼1·0) or high (≥1·0) baseline CD4+/CD8+ T cell ratios (P<0·01). The CD3+, CD4+ and CD8+ T cell counts of PLWH decreased significantly after vaccination (P<0·0001), but it did not lead to any adverse clinical manifestation. Moreover, we found that the general HIV-1 viral load among the PLWH cohort decreased significantly after vaccination (P=0·0192). The alteration of HIV-1 viral load was not significantly associated with the vaccine induced CD4+ T cell activation (P>0·2).InterpretationOur data demonstrated that the inactivated SARS-CoV-2 vaccine was safe, immunogenic in PLWH who are stable on cART with suppressed viral load and CD4+ T cell count > 200 cells/μL. However, the persistence of the vaccine-induced immunities in PLWH need to be further investigated.

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

PROLONGED COVID-19 IN PATIENTS TREATED WITH RITUXIMAB

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Patients with COVID-19 who have been prescribed rituximab prior to SARS-CoV-2 infection may be susceptible to an alternative disease course compared to the general population. These patients can develop chronic fatigue, dyspnea, fevers, and persistent radiographic abnormalities after appearing to convalesce from their index infection. CASE PRESENTATION: We report a case series of 3 patients with prolonged COVID-19 infections who had received rituximab prior to their index SARS-CoV-2 infection. They were all successfully treated with a combination of remdesivir and antibody therapy. This report demonstrates and replicates successful application of anti-viral therapy with remdesivir, and the provision of convalescent plasma/monoclonal antibodies to thwart B-cell depletion to treat patients with prolonged COVID-19 symptoms. DISCUSSION: Rituximab can cause B-cell depletion, impairment in humoral immunity, and delayed viral clearance with persistent viremia. Intact humoral and innate immunity appear necessary to eradicate SARS-CoV-2 in some individuals being treated with rituximab. The American Society of Hematology reports on 17 B-cell depleted patients with prolonged COVID-19 who were treated with convalescent plasma. All but 1 patient had symptom improvement within 48 hours. These findings support our experience and suggest that combination antiviral and antibody therapy is a promising treatment strategy. The reporting of successful and safe treatment strategies are crucial to guide clinicians as it is unlikely that there will be large, randomized control trials examining optimal therapeutic strategies for patients with a lack of humoral protection. CONCLUSIONS: Patients with COVID-19 who had been prescribed rituximab prior to infection may be susceptible to chronic symptoms with persistent radiographic features. Combination antiviral and antibody therapy is a promising treatment strategy in this cohort. REFERENCE #1: Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020;136:2290-5 REFERENCE #2: Helleberg M, Niemann CU, Moestrup KS, et al. Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of Remdesivir Therapy. J Infect Dis 2020;222:1103-7 DISCLOSURES: No relevant relationships by Rachel Aviv, source=Web Response No relevant relationships by Effie Singas, source=Admin input No relevant relationships by Andrew Weber, source=Web Response

Identification and Characterization of Rift Valley Fever Virus-Specific T Cells Reveals a Dependence on CD40/CD40L Interactions for Prevention of Encephalitis.

Rift Valley fever virus (RVFV) is an arbovirus found throughout Africa. It causes disease that is typically mild and self-limiting; however, some infected individuals experience severe manifestations, including hepatitis, encephalitis, or even death. Reports of RVFV encephalitis are notable among immunosuppressed individuals, suggesting a role for adaptive immunity in preventing this severe complication. This phenomenon has been modeled in C57BL/6 mice depleted of CD4 T cells prior to infection with DelNSs RVFV (RVFV containing a deletion of nonstructural protein NSs), resulting in late-onset encephalitis accompanied by high levels of viral RNA in the brain in 30% of animals. In this study, we sought to define the specific type(s) of CD4 T cells that mediate protection from RVFV encephalitis. The viral epitopes targeted by CD4 and CD8 T cells were defined in C57BL/6 mice, and tetramers for both CD4 and CD8 T cells were generated. RVFV-specific CD8 T cells were expanded and of a cytotoxic and proliferating phenotype in the liver following infection. RVFV-specific CD4 T cells were identified in the liver and spleen following infection and phenotyped as largely Th1 or Tfh subtypes. Knockout mice lacking various aspects of pathways important in Th1 and Tfh development and function were used to demonstrate that T-bet, CD40, CD40L, and major histocompatibility complex class II (MHC-II) mediated protection from RVFV encephalitis, while gamma interferon (IFN-γ) and interleukin-12 (IL-12) were dispensable. Virus-specific antibody responses correlated with protection from encephalitis in all mouse strains, suggesting that Tfh/B cell interactions modulate clinical outcome in this model. IMPORTANCE The prevention of RVFV encephalitis requires intact adaptive immunity. In this study, we developed reagents to detect RVFV-specific T cells and provide evidence for Tfh cells and CD40/CD40L interactions as critical mediators of this protection.

Toxoplasma Pericarditis in an Immunocompetent Child- A Rare Case Report

Toxoplasmosis is a parasitic infection caused by the protozoan, Toxoplasma gondii which is an obligate intracellular parasite. Among all the parasites known to cause myocarditis or pericarditis, the most commonly found is Chaga’s Disease or American Trypanosomiasis. Several other parasites including T. gondii can affect the heart in immunocompromised patients. Individuals with intact immunity largely remain asymptomatic. Only 22 cases of Toxoplasma Pericarditis have been reported worldwide.&#x0D; Although, CNS and Ocular Toxoplasmosis cases have been reported from Indian subcontinent, there is a lack of literature on cardiac involvement by Toxoplasma. Here, we present a case of a 11 yr old immunocompetent child with Toxoplasma Pericarditis, the first case to be reported from India. An echocardiography confirmed diagnosis of pericardial effusion for which pericardiocentesis was done and sent to our department for cytological evaluation. Fluid was exudative with pericardial fluid to serum protein ratio of 0.7. Gram stain, AFB stain and CB NAAT of pericardial fluid were negative. Cytology revealed neutrophils and macrophages showing presence of intracellular organisms resembling tachyzoites of Toxoplasma species on the Giemsa stained smear. These tachyzoites were crescent shaped with one pointed end and the other rounded end and a central nuclei.&#x0D; A final diagnosis of Toxoplasma Pericarditis was made based on microscopy findings. T. gondii serological tests were also done which showed positivity for IgG with strong avidity. Thus, our case report represents an important differential that should be considered by all the clinicians in cases of acute pericarditis, especially in difficult cases where no other cause can be identified.