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Outcomes of Patients with Sarcoma and COVID-19 Infection: A Single Institution Cohort Analysis

Cancer Invest

2021 Seth Pollack; Lee Cranmer; Petros Grivas; Gary Lyman; Matthew Thompson; Michael Wagner; Margaret Madeleine; Ali Khaki; Elizabeth Loggers

Outcomes for patients (pts) with sarcoma and COVID-19 are unknown. This is a single institution retrospective study of adults with sarcoma and COVID-19. Ten pts [median age 60 (range 24-69)] were identified. Five were hospitalized; two died from COVID-19 complications; another died from sarcoma. Time between last systemic treatment dose and COVID-19 diagnosis was 6-41 days in pts who died. 5 underwent prior radiation (RT); time between RT and COVID-19 diagnosis was 20-62 days for pts who died. All three pts with WBC differential data (2 died) were lymphopenic. Efforts to capture outcomes for a larger cohort are urgently needed.

Immunogenicity of CAR T cells in cancer therapy

Nat Rev Clin Oncol

2021 Cameron Turtle

Patient-derived T cells genetically reprogrammed to express CD19-specific chimeric antigen receptors (CARs) have shown remarkable clinical responses and are commercially available for the treatment of patients with certain advanced-stage B cell malignancies. Nonetheless, several trials have revealed pre-existing and/or treatment-induced immune responses to the mouse-derived single-chain variable fragments included in these constructs. These responses might have contributed to both treatment failure and the limited success of redosing strategies observed in some patients. Data from early phase clinical trials suggest that CAR T cells are also associated with immunogenicity-related events in patients with solid tumours. Generally, the clinical implications of anti-CAR immune responses are poorly understood and highly variable between different CAR constructs and malignancies. These observations highlight an urgent need to uncover the mechanisms of immunogenicity in patients receiving CAR T cells and develop validated assays to enable clinical detection. In this Review, we describe the current clinical evidence of anti-CAR immune responses and discuss how new CAR T cell technologies might impact the risk of immunogenicity. We then suggest ways to reduce the risks of anti-CAR immune responses to CAR T cell products that are advancing towards the clinic. Finally, we summarize measures that investigators could consider in order to systematically monitor and better comprehend the possible effects of immunogenicity during trials involving CAR T cells as well as in routine clinical practice.

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease

Semin Immunopathol

2021 David Granadier; Lorenzo Iovino; Sinéad Kinsella; Jarrod Dudakov

T cell recognition of unknown antigens relies on the tremendous diversity of the T cell receptor (TCR) repertoire; generation of which can only occur in the thymus. TCR repertoire breadth is thus critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, thymic function is exquisitely sensitive to negative stimuli, which can come in the form of acute insult, such as that caused by stress, infection, or common cancer therapies; or chronic damage such as the progressive decline in thymic function with age. Whether it be prolonged T cell deficiency after hematopoietic cell transplantation (HCT) or constriction in the breadth of the peripheral TCR repertoire with age; these insults result in poor adaptive immune responses. In this review, we will discuss the importance of thymic function for generation of the TCR repertoire and how acute and chronic thymic damage influences immune health. We will also discuss methods that are used to measure thymic function in patients and strategies that have been developed to boost thymic function.

Targeting the membrane-proximal C2-set domain of CD33 for improved CD33-directed immunotherapy


2021 Colin Correnti; Salvatore Fiorenza; Cameron Turtle; Roland Walter; George Laszlo; Eliotte Garling; Margaret Lunn; Olivia Bates; Colin Godwin; Olivier Humbert; Hans-Peter Kiem; Benjamin Hoffstrom; Tinhdoan Phi

There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics. As one limitation, CD33 antibodies typically recognize the membrane-distal V-set domain. Using various artificial CD33 proteins, in which this domain was differentially positioned within the extracellular portion of the molecule, we tested whether targeting membrane-proximal epitopes enhances the effector functions of CD33 antibody-based therapeutics. Consistent with this idea, a CD33V-set/CD3 bispecific antibody (BsAb) and CD33V-set-directed chimeric antigen receptor (CAR)-modified T cells elicited substantially greater cytotoxicity against cells expressing a CD33 variant lacking the entire C2-set domain than cells expressing full-length CD33, whereas cytotoxic effects induced by GO were independent of the position of the V-set domain. We therefore raised murine and human antibodies against the C2-set domain of human CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain ("CD33PAN antibodies"). These antibodies internalized when bound to CD33 and, as CD33PAN/CD3 BsAb, had potent cytolytic effects against CD33+ cells. Together, our data provide the rationale for further development of CD33PAN antibody-based therapeutics.

Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model

Life Sci Alliance

2021 Christina Leverich; Robert Pierce; Nina Salama; Julien Dubrulle; Valerie O'Brien; Jean Campbell; Vattanak Kong; Amanda Koehne; Armando Rodriguez

More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.

Combination Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma-Reply

JAMA Oncol

2021 Lee Cranmer; Seth Pollack; Michael Wagner


Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary

Future Oncol

2020 Ulrike Peters; John Thompson; Joshua Veatch; Evan Hall; Allison Silverman; Sylvia Lee; Rachel Malen; Amanda Phipps; Scott Tykodi; Shailender Bhatia; Arthur Sillah

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

Associations between the Gut Microbiota, Immune Reconstitution, and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation


2021 Salvatore Fiorenza; Cameron Turtle

Immune reconstitution following allogeneic hematopoietic stem cell transplantation (allo-HSCT) sets the stage for the goal of a successful transplant-the prevention of disease relapse without graft versus host disease (GVHD) and opportunistic infection. In both epidemiologic studies and in controlled animal studies, it is known that the gut microbiome (GM) can profoundly influence normal innate and adaptive immune development and can be altered by microbial transfer and antibiotics. Following allo-HSCT the GM has been shown to influence clinical outcomes but published associations between the GM and immune reconstitution post-allo-HSCT are lacking. In this viewpoint we propose that the extensive knowledge garnered from studying normal immune development can serve as a framework for studying immune development post-allo-HSCT. We summarize existing studies addressing the effect of the GM on immune ontogeny and draw associations with immune reconstitution and the GM post-allo-HSCT.

Building the Next Generation of Humanized Hemato-Lymphoid System Mice

Front Immunol

2021 Jonathan Linton; Wei Tan; Kelly McKenna; Tayla Olsen; Anthony Rongvaux; Emily Collins-Rice; Allie Kehret; Tijana Martinov; Nour Shobaki

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these "humanized" mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

Short H2A histone variants are expressed in cancer

Nat Commun

2021 Marie Bleakley; Robert Bradley; Guo-Liang Chew; Harmit Malik; Jay Sarthy; Steven Henikoff; Antoine Molaro

Short H2A (sH2A) histone variants are primarily expressed in the testes of placental mammals. Their incorporation into chromatin is associated with nucleosome destabilization and modulation of alternate splicing. Here, we show that sH2As innately possess features similar to recurrent oncohistone mutations associated with nucleosome instability. Through analyses of existing cancer genomics datasets, we find aberrant sH2A upregulation in a broad array of cancers, which manifest splicing patterns consistent with global nucleosome destabilization. We posit that short H2As are a class of "ready-made" oncohistones, whose inappropriate expression contributes to chromatin dysfunction in cancer.