Dual-Specificity CAR+ T Cells to Target B-Cell Malignancies and Opportunistic Fungal Infection

Abstract

CTL was characterized as to eps specificity and restricting HLA allele. The pool of CTL donors inherited HLA alleles in frequencies similar to those in caucasian and black populations, with certain alleles overrepresented. In 55% of the CTL lines, the ID T-cell response (TCr) was restricted (restr.) by 3 HLA alleles: A0201(25%), B0702(21%) and B 3501-11(9%); 45% of CTL lines were restr. by other class-I alleles, and 17/123(14%) were restr. by class-II alleles. Certain CMVpp65 15 mers contained overlapping eps presented by both class-I and class-II, which elicited more robust TCr. CTLs from all B0702 + donors (26/26) were restr. by B0702. In comparison, CTLs from 30/39(77%) A0201 + donors and 9/19 (47%) HLA B3501-11 + donors were restr. by A0201 and B3501-11 respectively. Donors coinheriting A0201 and B 0702 (9/9) universally demonstrated B0702 restr. ID TCr. In comparison, 11/12 (91.6%) donors coinheriting A0201 and B 4401-04 demonstrated HLA A0201 restr. CTLs. Strikingly, only 1/123 and 0/123 A1101 + and A0301 + donors respectively demonstrated CTLs restr. by these commonly inherited class eI alleles. This analysis thus indicates an immunodominance hierarchy for CMVpp65 eps and their presenting HLA alleles. In a series of 239 MUD, 137 MMUD, and 100 DUCB consecutive HSCT at MSKCC, we could identify an immediately available CMVpp65 specific CTL line matched with the patient at 2-3 alleles and restr. by a shared HLA allele in this GMP-CTL bank in 86%, 89% and 80% cases respectively. This CTL bank thus provides a clinical reagent for the treatment of CMV infections in HSCT recipients. The delineated immunodominance hierarchy for CMVpp65 may also facilitate selection of an appropriately restr. CTL line for treatment with predicted activity in the recipient. We can also successfully generate CMV-CTLs against subdominant CMVpp65 eps presented prevalent HLA alleles using a panel of artificial antigen presenting cells (AAPCs). Expansion of this bank with CTLs generated with AAPCs can broaden its applicability to almost all HSCT recipients.

Engraftment, fate, and function of HoxB8-conditional neutrophil progenitors in the unconditioned murine host

“…Due to a number of factors, the pipeline for new antibiotics has seen a drastic reduction in productivity (Lewis, 2013). Immunomodulatory and cell therapeutic strategies are being pursued as a complementary approach or alternative to antibiotics (Hancock et al, 2012;Kumaresan et al, 2014). While granulocyte transfusion therapy has experienced a long and detoured path in clinical implementation (Marfin and Price, 2015), it may be worth revisiting its conceptual basis as new approaches are developed for generating neutrophils (both ex vivo and in vivo).…”

New Treatment Regime for Aspergillus Mediated Infections

“…They are the causative agent of pulmonary or invasive aspergillosis, or various allergic manifestations such as allergic bronchopulmonary aspergillosis (ABPA) [1]. The mortality rate is 60% to 85% in hematopoietic stem cell transplant patients and 22% in patients having solid organ transplant [2]. The emergence of drug resistance Aspergillus species possess a new threat to these individuals.…”

“…Kumaresean et al use the sleeping beauty (SB) transposon/ transposase system to develop such cells. T-cells having these designated chimeric antigen receptors (D-CAR) have specificity for β-glucan and thus lead to damage of Aspergillus hyphae [2].…”

Checkpoint inhibitors as immunotherapy for fungal infections: Promises, challenges, and unanswered questions

“…Over the past 20 years, many groups designed cellular immune therapeutics to restore and augment antifungal immunity, including adoptive T cell transfer, chimeric antigen receptor T cells, ex-vivo-pulsed dendritic cells (DCs), and azoleloaded neutrophils (7)(8)(9)(10)(11)(12). However, despite a multitude of promising preclinical data, only few of these approaches eventually entered small-scale clinical studies, which is not surprising, as cellular immune therapeutics are costly, difficult to scale, time-and labor-intensive, logistically challenging, and subject to considerable regulatory hurdles (11,12).…”