Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR-T-cell treatment

Inflammation plays an important role in CAR-T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR-T-cell treatment is currently widely unknown. We longitudinally evaluated the prevalence of CHIP, using a targeted deep sequencing approach in a cohort of patients with r/r B-NHL before and after CAR-T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34 %) before CAR-T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR-T-cell treatment but had an improved OS (not reached vs. 265 days, p=0.003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic usage of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (except ferritin) or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR-T-cell therapy and is not associated with an inferior outcome.

Breast Cancer Tumor Microenvironment and Molecular Aberrations Hijack Tumoricidal Immunity

Breast cancer is the most common malignancy among females in western countries, where women have an overall lifetime risk of >10% for developing invasive breast carcinomas. It is not a single disease but is composed of distinct subtypes associated with different clinical outcomes and is highly heterogeneous in both the molecular and clinical aspects. Although tumor initiation is largely driven by acquired genetic alterations, recent data suggest microenvironment-mediated immune evasion may play an important role in neoplastic progression. Beyond surgical resection, radiation, and chemotherapy, additional therapeutic options include hormonal deactivation, targeted-signaling pathway treatment, DNA repair inhibition, and aberrant epigenetic reversion. Yet, the fatality rate of metastatic breast cancer remains unacceptably high, largely due to treatment resistance and metastases to brain, lung, or bone marrow where tumor bed penetration of therapeutic agents is limited. Recent studies indicate the development of immune-oncological therapy could potentially eradicate this devastating malignancy. Evidence suggests tumors express immunogenic neoantigens but the immunity towards these antigens is frequently muted. Established tumors exhibit immunological tolerance. This tolerance reflects a process of immune suppression elicited by the tumor, and it represents a critical obstacle towards successful antitumor immunotherapy. In general, immune evasive mechanisms adapted by breast cancer encompasses down-regulation of antigen presentations or recognition, lack of immune effector cells, obstruction of anti-tumor immune cell maturation, accumulation of immunosuppressive cells, production of inhibitory cytokines, chemokines or ligands/receptors, and up-regulation of immune checkpoint modulators. Together with altered metabolism and hypoxic conditions, they constitute a permissive tumor microenvironment. This article intends to discern representative incidents and to provide potential innovative therapeutic regimens to reinstate tumoricidal immunity.

Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.

The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections.

Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

Immunotherapeutic Peptide Vaccine Approaches to Glioma

Heretofore, there are no FDA-approved immunotherapeutics for malignant gliomas despite many novel therapies currently in different stages of clinical trials. Malignant gliomas are immunosuppressive tumors and are difficult for immune effector cells to infiltrate the tumor sites in the central nervous system. This inefficiency results in median survival of about only two years with a few long-term survivors. Recent clinical trials of vaccine-based immunotherapies against malignant gliomas have demonstrated encouraging results in enhancing progression-free survival and overall survival of patients. The vaccine-based treatments include peptide and heat-shock proteins, dendritic cell-based vaccines, as well as viral-based immunotherapy. In this review, we will focus on recent clinical trials of neoantigen peptide vaccines on gliomas, the delivery routes of such peptide vaccines, their adjuvants, clinical challenges, and its future strategies, respectively.

Fc-engineered antibodies with immune effector functions completely abolished

Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been described in the literature but none of them completely eliminates binding to all of the Fcγ receptors. Here we describe a set of novel variants having specific amino acid substitutions in the Fc region at L234 and L235 combined with the substitution G236R. They show no detectable binding to Fcγ receptors or to C1q, are inactive in functional cell-based assays and do not elicit inflammatory cytokine responses. Meanwhile, binding to FcRn, manufacturability, stability and potential for immunogenicity are unaffected. These variants have the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. However, the complex interplay between protective antifungal immunity and immunopathology remains incompletely understood. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that Epha2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 limits IL-23 secretion in dendritic cells, while IL-23 signaling prevents ferroptotic myeloid cell death during infection. Further, ferroptosis aggravates inflammation during infection, while at the same time reducing the fungal killing capacity of macrophages. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

Managing therapy-associated neurotoxicity in children with ALL

Several chemotherapeutic agents and novel immunotherapies provide excellent control of systemic and central nervous system (CNS) leukemia but can be highly neurotoxic. The manifestations of subacute methotrexate neurotoxicity are diverse and require vigilant management; nonetheless, symptoms are transient in almost all patients. As methotrexate is a crucial drug to prevent CNS relapse, it is important to aim to resume it after full neurologic recovery. Most children tolerate methotrexate rechallenge without significant delays or prophylactic medications. Neurotoxicity is more frequent with newer immunotherapies such as CD19– chimeric antigen receptor T (CAR T) cells and blinatumomab. A uniform grading system for immune effector cell–associated neurotoxicity syndrome (ICANS) and algorithms for management based on severity have been developed. Low-grade ICANS usually resolves within a few days with supportive measures, but severe ICANS requires multispecialty care in the intensive care unit for life-threatening seizures and cerebral edema. Pharmacologic interventions include anticonvulsants for seizure control and glucocorticoids to reduce neuroinflammation. Anticytokine therapies targeted to the pathophysiology of ICANS are in development. By using illustrative patient cases, we discuss the management of neurotoxicity from methotrexate, CAR T cells, and blinatumomab in this review.

Relapsed ALL: CAR T vs transplant vs novel therapies

Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.