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The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR) modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B cell non-Hodgkin lymphoma (B-NHL). Early phase clinical trials are presently assessing CAR T cell safety and efficacy in additional malignancies. Herein, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors, and highlight challenges and opportunities afforded by the current state of CAR T cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.

Background We aimed to characterize institutional resources utilized (other than T cell collection and CAR T cell manufacturing and infusion) peri-chimeric antigen receptor-modified (CAR) T cells administration. Methods Adult patients treated on selected investigator-initiated clinical trials of CAR T cell therapy at Memorial Sloan Kettering Cancer Center were identified from the institutional database. Utilization data was collected from the start of admission for CAR T cell infusion through the end of the initial admission for infusion or through 30 days following initial CAR T cell infusion, whichever was longer. Descriptive statistics were used to analyze the data. Results Between 6/2007 to 4/2018, 106 pts (56 pts (53%) B-cell acute lymphoblastic leukemia (ALL), 37 (35%) chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), and 13 (12%) multiple myeloma (MM)) on 4 clinical trials receiving inpatient CAR T cell infusions. The median age was 53 yrs (range 22-77) with 65% male. The median length of stay for the admission during which CAR T cells was given was 23 days (range 4 -133), with ALL patients admitted longer (Figure 1). 43 (41%) spent at least one day in the intensive care unit (ICU), with a range of 0-43 days. Outpatient clinic visits through day 30 post CAR T cell infusion occurred in 57 (53%) patients. A total of 62,953 laboratory panels and 1,190 radiology studies done during the study time frame. Fourteen percent of the labs were complete blood counts, basic or comprehensive metabolic panels, or liver function tests. For the total population, ALL, CLL/NHL, MM, there were a median of 63.5 (range 13-368), 91.5 (21-368), 47 (13-167), and 51 (range 38-113) of these panels done per patient during the time frame, respectively. Among the radiology studies, 25% were CT scans, 10% MRIs, 7% PET scans, 5% ultrasounds, and 53% x-rays, with differences in patterns of use by disease type (Figure 2). Chemotherapy accounted for 328 units (0.8%) of the 41,331 units of medications given in this time frame. The median medication units per patient was 255 (range 35-2091), 423 (range 35-2091), 200 (range 41-1190), and 207 (range 90-666) for the total population, and the ALL, CLL/NHL, and MM pts, respectively. Thirty-two doses of tocilizumab were given to 25 patients (24%), with ALL pts receiving 23 of those doses (72%). Conclusion CAR T cell therapy utilizes many resources and can create challenges in institutional resource capacity. Identifying these resources will allow for better allocation and care delivery. Further refinement of CAR T cell products and improvements in CAR T cell-related toxicity management may permit safer delivery of this therapy and reduce costs per patient. Comparison with alternative therapies and analysis of resource utilization for the commercial CAR T cell products is warranted.

Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P = .001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P

The past 20 years of experience with umbilical cord blood transplantation have demonstrated that cord blood is effective in the treatment of a spectrum of diseases, including hematological malignancies, bone marrow failure, hemoglobinopathies, and inborn errors of metabolism. Cord blood can be obtained with ease and then safely cryopreserved for either public or private use without loss of viability. As compared to other unrelated donor cell sources, cord blood transplantation allows for greater human leukocyte antigen disparity without a corresponding increase in graft-vs.-host disease. Moreover, cord blood has a lower risk of transmitting infections by latent viruses and is less likely to carry somatic mutations than other adult cells. Recently, multiple populations of stem cells with primitive stem cell properties have been identified from cord blood. Meanwhile, there is an increasing interest in applying cord blood mononuclear cells or enriched stem cell populations to regenerative therapies. Accumulating evidence has suggested functional improvements after cord blood transplantation in various animal models for treatments of cardiac infarction, diabetes, neurological diseases, etc. In this review, we will summarize the most recent updates on clinical applications of cord blood transplantation and the promises and limitations of cell-based therapies for tissue repair and regeneration.