Microbial cancer immunotherapy reprograms hematopoietic stem cells to enhance anti-tumor immunity.

Mycobacterium bovis BCG is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC-reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder in both mice and humans reprograms HSPCs to amplify myelopoiesis and functionally enhance myeloid cell antigen presentation pathways. Reconstitution of naive mice with HSPCs from bladder BCG-treated mice enhances anti-tumor immunity and tumor control, increases intratumor dendritic cell infiltration, reprograms pro-tumorigenic neutrophils, and synergizes with checkpoint blockade. We conclude that bladder BCG acts systemically, reprogramming HSPC-encoded innate immunity, highlighting the broad potential of modulating HSPC phenotypes to improve tumor immunity.

BCG-Induced Tumor Immunity Requires Tumor-Intrinsic CIITA Independent of MHC-II.

For decades, BCG immunotherapy has been the standard of care for non-muscle-invasive bladder cancer. Despite this clinical experience, the mechanism by which BCG stimulates tumor-eliminating immunity is unclear, and there is still a need for more accurate prediction of clinical outcomes in advance of treatment initiation. We have shown that BCG stimulates tumor-specific T-cell immunity that requires tumor cell expression of the IFNγ receptor (IFNGR); however, the downstream components of IFNGR signaling responsible for responsiveness to BCG are unknown. Here, we demonstrate that the IFNγ-driven, tumor cell intrinsic expression of the class II transactivator CIITA is required for activation of a tumor-specific CD4 T-cell response and BCG-induced tumor immunity. Despite the established role for CIITA in controlling MHC-II antigen presentation machinery, the requirement for CIITA is independent of MHC-II and associated genes. Rather, we find that CIITA is required for a broader tumor-intrinsic transcriptional program linked to critical pathways of tumor immunity via mechanisms that remain to be determined. Tumor cell intrinsic expression of CIITA is not required for a response to immunotherapy targeting programmed cell death protein 1 (PD-1), suggesting that different modalities of immunotherapy for bladder cancer could be employed based on tumor-intrinsic characteristics.

BCG in Bladder Cancer Immunotherapy.

BCG is a live attenuated strain of Mycobacterium bovis that is primarily used as a vaccine against tuberculosis. In the past four decades, BCG has also been used for the treatment of non-muscle invasive bladder cancer (NMIBC). In patients with NMIBC, BCG reduces the risk of tumor recurrence and decreases the likelihood of progression to more invasive disease. Despite the long-term clinical experience with BCG, its mechanism of action is still being elucidated. Data from animal models and from human studies suggests that BCG activates both the innate and adaptive arms of the immune system eventually leading to tumor destruction. Herein, we review the current data regarding the mechanism of BCG and summarize the evidence for its clinical efficacy and recommended indications and clinical practice.

Serial interferon-gamma release assay in lung cancer patients receiving immune checkpoint inhibitors: a prospective cohort study.

Recent advancements in cancer immunotherapy using immune checkpoint inhibitors (ICIs) have received considerable attention. Although advantageous, ICI therapies cause unique immune-related adverse events (irAEs) in some patients. Moreover, infectious diseases, such as tuberculosis, have been recognized as emerging concerns during immunotherapy. We aimed to evaluate the interferon-gamma release assay (IGRA) conversion rate and active tuberculosis incidence during immunotherapy to elucidate the incidence of tuberculosis reactivation after ICI therapy induction.We prospectively assessed IGRA results in lung cancer patients who received ICI monotherapy before ICI treatment and at 6 and 12 months after ICI treatment. We also assessed computed tomography findings to determine the presence of active tuberculosis when positive IGRA results were obtained. The ICIs used were nivolumab, pembrolizumab, atezolizumab, and durvalumab.In all, 178 patients were prospectively recruited between March 2017 and March 2020. Of these, 123 completed serial IGRAs, of whom 18, 101, and 4, respectively, had positive, negative, and indeterminate IGRAs at baseline. Three and four patients, respectively, showed IGRA reversion and conversion during immunotherapy. One patient with a sustained, stable positive IGRA and one with IGRA conversion developed active pulmonary tuberculosis during immunotherapy.We found that 3.3% and 1.6% of the patients developed IGRA conversion and active tuberculosis, respectively. Of the four patients who developed IGRA conversion, one developed active pulmonary tuberculosis during immunotherapy. Another patient with sustained, stable positive IGRA developed active tuberculosis. Physicians should be alert to tuberculosis development during ICI therapy, and IGRA testing is a useful tool to assess the risk of developing active tuberculosis.

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

Abdominal imaging findings on computed tomography in patients acutely infected with SARS-CoV-2: what are the findings?

OBJECTIVES: To investigate what findings are new on contrast-enhanced abdominopelvic CT in patients infected with SARS-CoV-2. METHODS: Contrast-enhanced CT of the abdomen and pelvis of patients with COVID-19 at a tertiary oncologic center acquired over a 2-month period were reviewed independently by two readers and scored for new imaging abnormalities compared with a prior scan. CT scans were included if the study was performed between - 3 and 45 days from the time of COVID-19 diagnosis. Clinical information was gathered from the medical records. RESULTS: A total of 63 patients (34 male, 29 female; mean age 60.6 years, range 24.4-85.0 years) were included in this retrospective cross-sectional study. Aside from new ground glass opacities seen at the lung bases (29/63, 46.0%), the most common findings were new thickening of the stomach, small bowel or colon or fluid-filled colon (14/63, 22.2%), new small volume ascites (7/63, 14.3%), gallbladder distention in those without prior cholecystectomy (3/43, 7.0%), and single cases each of acute pancreatitis (1/63, 1.6%) as well as new portal vein thrombosis (1/63, 1.6%). CONCLUSION: Aside from lung base ground glass opacities, the most common new imaging abnormality on abdominopelvic CT in patients with COVID-19 finding in our cohort was abnormalities of the gastrointestinal tract, followed by small volume ascites, gallbladder distention, and isolated cases of pancreatitis and portal vein thrombosis. These findings overlap with those previously reported that did not have a prior scan for comparison, and provide supportive evidence that some of these findings may be related to SARS-CoV-2 infection.

Recommendations for Testing and Treating Outpatient Cancer Patients in the Era of COVID-19.

The clinical spectrum of coronavirus disease 2019 (COVID-19) is still not fully understood. Cancer patients are uniquely vulnerable to COVID-19, and many have been or will be infected. Although an unfortunate minority will die from the infection, most will recover. This poses a challenge in which clinicians must weigh the benefits of initiation or resumption of antineoplastic therapy against the risks that antineoplastic treatment may worsen outcomes related to COVID-19 infection. A recent study of 423 patients at our institution found that patients in active cancer treatment who develop COVID-19 infection did not fare any worse than other hospitalized patients, yet guidance as to who requires testing prior to antineoplastic therapy and when to resume therapy post-COVID-19 diagnosis remains unknown. Our institution, therefore, commissioned a task force to help create guidelines for treating oncologists using available published literature. The task force focused on the ambulatory care testing guidelines only, because all inpatients receiving antineoplastic therapy are tested for COVID-19 prior to hospital admission. The guidelines focus solely on the safety and well-being of the individual patient undergoing antineoplastic therapy and are not designed to address infection control issues.

Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling.

Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer is the only bacterial cancer therapy approved for clinical use. Although presumed to induce T cell-mediated immunity, whether tumor elimination depends on bacteria-specific or tumor-specific immunity is unknown. Herein we show that BCG-induced bladder tumor elimination requires CD4 and CD8 T cells, although augmentation or inhibition of bacterial antigen-specific T cell responses does not alter the efficacy of BCG-induced tumor elimination. In contrast, BCG stimulates long-term tumor-specific immunity that primarily depends on CD4 T cells. We demonstrate that BCG therapy results in enhanced effector function of tumor-specific CD4 T cells, mainly through enhanced production of IFN-γ. Accordingly, BCG-induced tumor elimination and tumor-specific immune memory require tumor cell expression of the IFN-γ receptor, but not MHC class II. Our findings establish that a bacterial immunotherapy for cancer is capable of inducing tumor immunity, an antitumor effect that results from enhanced function of tumor-specific CD4 T cells, and ultimately requires tumor-intrinsic IFN-γ signaling, via a mechanism that is distinct from other tumor immunotherapies.

Determinants of Severity in Cancer Patients with COVID-19 Illness.

New York State had 180,458 cases of SARS-CoV-2 and 9385 reported deaths as of April 10th, 2020. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher COVID-19 death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19 disease4. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. Since March 10th, 2020 Memorial Sloan Kettering Cancer Center performed diagnostic testing for SARS-CoV-2 in symptomatic patients. Overall, 40% out of 423 patients with cancer were hospitalized for COVID-19 illness, 20% developed severe respiratory illness, including 9% that required mechanical ventilation, and 9% that died. On multivariate analysis, age ≥ 65 years and treatment with immune checkpoint inhibitors (ICI) within 90 days were predictors for hospitalization and severe disease, while receipt of chemotherapy within 30 days and major surgery were not. Overall, COVID-19 illness is associated with higher rates of hospitalization and severe outcomes in patients with cancer. Association between ICI and COVID-19 outcomes will need interrogation in tumor-specific cohorts.

Determinants of COVID-19 disease severity in patients with cancer.

As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-194. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.

Complications of Intravesical BCG Immunotherapy for Bladder Cancer.

An earlier incorrect version appeared online. This article was corrected on December 14, 2018.

Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus.

Intratumoral therapy with oncolytic viruses is increasingly being explored as a strategy to potentiate an immune response against cancer, but it remains unknown whether such therapy should be restricted to cancers sensitive to virus-mediated lysis. Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates. Infection of human and mouse bladder cancer cells with NDV resulted in immunogenic cell death, activation of innate immune pathways, and upregulation of MHC and PD-L1 in all tested cell lines, including the cell lines completely resistant to NDV-mediated lysis. In a bilateral flank NDV-lysis-resistant syngeneic murine bladder cancer model, intratumoral therapy with NDV led to an increase of immune infiltration in both treated and distant tumors and a shift from an inhibitory to effector T cell phenotype. Consequently, combination of intratumoral NDV with systemic PD-1 or CTLA-4 blockade led to improved local and abscopal tumor control and overall survival. These findings encourage future clinical trials combining intratumoral NDV therapy with systemic immunomodulatory agents and underscore the rationale for such treatments irrespective of tumor cell sensitivity to NDV-mediated lysis.

The Canonical Wnt Pathway Drives Macropinocytosis in Cancer.

Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the ß-catenin-dependent canonical Wnt pathway, was PAK1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation.Significance: The Wnt pathway drives macropinocytosis in cancer cells, thereby contributing to cancer growth in nutrient-deficient conditions and, in the context of colon cancer, to the early phases of oncogenesis. Cancer Res; 78(16); 4658-70. ©2018 AACR.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods: We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. Results: We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Conclusions: Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.

The Spectrum of Serious Infections Among Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma.

The risk of infection among patients receiving immune checkpoint blockade is unknown. We retrospectively reviewed medical records of 740 patients with melanoma who received immune checkpoint blockers. Serious infection occurred in 54 patients (7.3%). The main risk factors were receipt of corticosteroids and/or infliximab.

The mechanism of action of BCG therapy for bladder cancer--a current perspective.

Bacillus Calmette-Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4(+) and CD8(+) lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells.

Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell.

IFN-γ release assays in the diagnosis of latent tuberculosis infection among immunocompromised adults.

Immunocompromised persons with latent tuberculosis infection (LTBI) are at increased risk for tuberculosis reactivation compared with the general population. The tuberculin skin test, the traditional assay for diagnosing LTBI, has reduced accuracy in immunocompromised patients. IFN-γ release assays (IGRAs) are in vitro blood tests that measure T-cell release of IFN-γ after stimulation with antigens unique to Mycobacterium tuberculosis. Here we review the data for the use of QuantiFERON-TB Gold In-Tube and T-SPOT.TB, the two currently available IGRAs, in immunocompromised adults, including persons infected with HIV, patients with immune-mediated inflammatory disorders, candidates for treatment with tumor necrosis factor-α inhibitors, patients receiving hemodialysis, solid-organ transplant recipients, and patients with cancer. On the basis of the available data, IGRAs have advantages over the tuberculin skin test in specific patient populations and in certain situations. Further studies are needed to more accurately define the usefulness of IGRAs in immunocompromised patients.

Inhibition of mycobacterial infection by the tumor suppressor PTEN.

The tumor suppressor PTEN is a lipid phosphatase that is frequently mutated in various human cancers. PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. In addition to it role in tumor suppression, the PTEN-PI3K pathway controls many cellular functions, some of which may be important for cellular resistance to infection. Currently, the intersection between tumorigenic signaling pathways and cellular susceptibility to infection is not well defined. In this study we report that PTEN signaling regulates infection of both noncancerous and cancerous cells by multiple intracellular mycobacterial pathogens and that pharmacological modulation of PTEN signaling can affect mycobacterial infection. We found that PTEN deficiency renders multiple types of cells hyper-susceptible to infection by Mycoplasma and Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The lipid phosphatase activity of PTEN is required for attenuating infection. Furthermore, we found mycobacterial infection activates host cell Akt phosphorylation, and pharmacological inhibition of Akt or PI3K activity reduced levels of intracellular infection. Intriguingly, inhibition of mTOR, one of the downstream components of the Akt signaling and a promising cancer therapeutic target, also lowered intracellular Bacillus Calmette-Guérin levels in mammary epithelial cancer MCF-7 cells. These findings demonstrate a critical role of PTEN-regulated pathways in pathogen infection. The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells.