Adverse events following infusion of T cells for adoptive immunotherapy: A 10-year experience

Background aims. The Food and Drug Administration (FDA) currently recommends at least 4 h of recipient monitoring after T cell infusions to detect early infusion reactions. Recent catastrophic reactions to 'first-in-man' biologic agents have emphasized the importance of this rule for initial studies of new products. The value of such monitoring for better established agents is less obvious. Methods. We reviewed infusion-related adverse events (AE) following administration of ex vivo-expanded T cell products (antigen-specific cytotoxic T lymphocytes, allodepleted T cells, and genetically modified T cells) on investigational new drug (IND) studies in our center. Results. From 1998 to 2008, we infused 381 T cell products to 180 recipients, enrolled on 18 studies, receiving T cells targeting malignancies or post-transplant viral infections. There were no grade 34 infusion reactions during initial monitoring or 24-h follow-up. Twenty-four mild (grade 12) AE occurred in 21 infusions either during or immediately following infusion (up to 6 h), most commonly nausea and vomiting (10/24, 41.6%), probably because of the dimethyl sulfoxide cryoprotectant, and hypotension (20.8%), attributable to diphenhydramine pre-medication. Twenty-two additional non-severe events were reported within 24 h of infusion, most commonly culture-negative fever, chills and nausea. An increased risk of adverse events was associated with age [incidence rate ratio (IRR) 0.98; 95% confidence interval (CI) 0.961.00, P 0.05], while an increased risk of immediate infusion-related events was higher in patients reporting allergies (IRR 2.72, 95% CI 1.007.40, P 0.05); sex, disease type and T cell source (allogeneic or autologous) had no effect on frequency of adverse events. Conclusions. Infusion of these T cell products was safe in the outpatient setting and associated with no severe reactions, so monitoring for 1 h after infusion is probably sufficient. As many of the AE were attributable to diphenhydramine premedication, a lower dose (0.25 mg/kg) should be selected

CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma

Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163+ myeloid cells (change from baseline, p = 0.0126) in all patients, which may have contributed to the modest early antitumor responses; the effect of these cells merits further study. Thus, CARTs are safe, and Cy/Flu can further increase their expansion

Inner hybridity in the city: Toward a critique of multiculturalism

Muddled as an idea and flawed as a public policy, multiculturalism in Canada advocates conformity to a unitary culture in the public place and tolerance of diverse cultures in the private place. This tolerance of cultural heterogeneity in the sphere of the intimate is often upheld as a defining characteristic of Canadian society. Yet multiculturalism is not without criticisms. For one, multiculturalism is at odds with the desire of the children and grandchildren of the Chinese immigrants in Canada to adapt themselves to their host society, thus transforming themselves as well as the laglecrv society. A multicultural policy that continues to hark back to the past turns a blind eye to the fierce generation and gender politics within the Chinese family. Neither does the multicultural policy square well with a more progressive social theory of self, identity, and culture that is cognizant of the duality of the psychological make-up of human beings: that one looks backward and forward, committed to preserving roots of the past and exploring routes to the future. As such, the Canadian multicultural policy suffers in a two-fold way: empirical and theoretical. A possible way out is to pursue a Hegelian dialectics that sees culture as an aftermath of a collision of dissimilar cultures, a kind of forced entanglement of things different We need a new urban social theory that sees integration, fusion, and hybridization—not assimilation, and not cultural pluralism—as possible and desirable outcomes. This is a completely different vision of society altogether, a kind of Utopia. We need a public policy that sees a distinct promise of the city in designing institutions and public spaces that promote hybridism in the mind, an inner deliberation, a mental turmoil—which is not afraid of confronting modern life's many moments of contradictions, ironies and paradoxes.Multiculturalism, pluralism, public/private divide, assimilation, hybridism,