From Naturally Occurring Tumor Immunity to Supernatural T Cells: Isolation and Characterization of a Murine T Cell Receptor Specific for Human Breast and Ovarian Tumor Antigen Cdr2

Patients with paraneoplastic cerebellar degeneration (PCD), a form of neuronal autoimmunity, have a co-occurring natural immune response against a protein called cdr2 in their breast and ovarian carcinomas, and thus provide an innovative starting point for understanding how to harness the immune system to fight cancer. We previously demonstrated cdr2-specific cytotoxic T lymphocytes (CTL) in the peripheral blood of HLA-A2.1+ PCD patients, suggesting that CTLs mediate tumor immunity in these patients. Cdr2 is expressed by a large proportion of breast and ovarian tumors from individuals who do not develop neurological disease, suggesting that immune responses to this antigen may develop independently of autoimmune responses. Here we explore establishing cdr2 as a target for breast and ovarian cancer immunotherapy by identifying naturally processed A2.1-restricted epitopes of cdr2. Immunization of A2.1 transgenic mice with recombinant adenovirus encoding human full length cdr2 led to the identification of two naturally processed A2.1-restricted human cdr2 peptides: cdr2(289-297) and cdr2(290-298). Mouse-derived A2.1-restricted cdr2(289-297)-specific CTLs were able to target cells expressing endogenous human cdr2, but also cross-reacted with endogenous mouse cdr2, resulting in partial tolerance to this epitope. In contrast, mouse-derived A2.1-restricted cdr2(290-298)-specific CTL were capable of recognizing tumor cells expressing endogenous human cdr2, but were unable to recognize mouse cdr2 due to nonhomology of the human and mouse cdr2(290- 298) epitopes. cdr2(290-298)-specific CTL clones were isolated, and their TCR gene cloned. Transfer of the mouse-derived TCR into human CD8+ T cells turned them into efficient cdr2-specific CTLs. We have detected CD8+ T cells specific for both cdr2(289-297) and cdr2(290-298) in peripheral blood from A2.1+ PCD patients by tetramer staining. This correlates the presence of T cells specific to these epitopes with PCD and effective anti-gynecologic tumor immunity, and suggests that these are bona fide tumor-associated CTL epitopes. We conclude swthat gene transfer of TCR specific for cdr2(290-298) could provide the basis for potent breast and ovarian cancer immunotherapies, while cdr2(289-297)-specific T cells, able to target both mouse and human cdr2, offer a platform for generating a humanized animal model to investigate the whether cdr2-TCR gene transfer is possible without inducing neuronal autoimmunity

How I treat unique and difficult-to-manage cases of CAR T-cell therapy–associated neurotoxicity

With growing indications for chimeric antigen receptor (CAR) T-cell therapy, toxicity profiles are evolving. There is an urgent and unmet need of approaches to optimally manage emerging adverse events that extend beyond the standard paradigm of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). Although management guidelines exist for ICANS, there is little guidance on how to approach patients with neurologic comorbidities, and how to manage rare neurotoxicity presentations, such as CAR T-cell therapy-related cerebral edema, severe motor complications or late-onset neurotoxicity. In this study, we present 3 scenarios of patients treated with CAR T cells who develop unique types of neurotoxicity, and we describe an approach for the evaluation and management based on experience because objective data are limited. The goal of this study is to develop an awareness of emerging and unusual complications, discuss treatment approaches, and help institutions and health care providers establish frameworks to navigate how to best address unusual neurotoxicities to ultimately improve patient outcomes

Multifocal and pathologically-confirmed brain metastasis complete response to trastuzumab deruxtecan

Antibody–drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood–brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody–drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation

BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (C-D), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (C-D = 0.89-0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with > 30% newly expanded TCRs (C-D = 0.56-0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response

Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit–risk profile for treatment of MM

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

•Cytokine release syndrome (CRS) and neurotoxicity are common after immune effector cell (IEC) therapy.•Neurotoxicity is now termed IEC-associated neurotoxicity syndrome (ICANS).•A consensus grading system for CRS and ICANS has been developed by experts in the field.•The grading system is designed for IEC therapies in clinical trials and commercial use.•Standardized reporting through the Center for International Blood and Marrow Transplant Research will meet commercial Risk Evaluation and Mitigation Strategies requirements. Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclas-sical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypi-cal features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous mem-branes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atyp-ical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features. (c) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients