AbstractChimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.
Despite remarkable achievements in the treatment of hematologic malignancies, chimeric antigen receptor (CAR)-T cell therapy still faces many obstacles. The limited antitumor activity and persistence of infused CAR-T cells, especially in solid tumors, are the main limiting factors for CAR-T therapy. Moreover, clinical security and accessibility are important unmet needs for the application of CAR-T therapy. In view of these challenges, many potentially effective solutions have been proposed and confirmed. Both the independent and combined strategies of CAR-T therapy have exhibited good application prospects. Thus, in this review, we have discussed the cutting-edge breakthroughs in CAR-T therapy for cancer treatment, with the aim of providing a reference for addressing the current challenges.
PURPOSE: Intravenous immunoglobulin (IVIG) is used to replenish immunoglobulins in hypogammaglobulinemia (HG) caused by hematologic malignancies (HM) or their treatment (autologous stem-cell transplantation [ASCT] and chimeric antigen receptor T-cell therapy [CAR-T]), in an effort to reduce the risk of infections. However, there is limited evidence to support this use, and IVIG supplies are limited and shortages are common. METHODS: An IVIG stewardship program (ISP) was implemented with the following requirements for IVIG administration: immunoglobulin G (IgG) level < 400 mg/dL (corrected for paraprotein) for post-ASCT and post–CAR-T patients, or IgG < 400 mg/dL with a history of a bacterial infection within the preceding 3 months for those with HM. Comparisons of the amount of IVIG administered, the incidence of infections, and the use of antimicrobials were performed between the 3 months before ISP and the 3 months after ISP. RESULTS: IVIG administered for HG decreased from 4,902 g in 86 patients before ISP to 1,777 g in 55 patients after ISP, a cost savings of $44,700. Adherence to ISP guidelines was 80%. Compared with before ISP, patients who stopped receiving IVIG after ISP had lower nadir IgG, fewer infections/patient-months, less antimicrobial usage, and a lower hospitalization rate for infection; no deaths occurred. Compared with before ISP, patients receiving IVIG after ISP had lower predose IgG and fewer infections/patient-months; the antibiotic usage, hospitalization rate for infection, and deaths from infection remained stable. CONCLUSION: To our knowledge, this is the first ISP to lead to a dramatic decrease in IVIG usage with high adherence, primarily by selecting out patients at low risk of infection after IVIG discontinuation. Such an ISP is replicable and warrants adoption.
Allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T cell (CAR T) therapy are the main modalities of adoptive cellular immunotherapy that have widely permeated the clinical space. The advent of both technologies revolutionized treatment of many hematologic malignancies, both offering the chance at sustained remissions for patients who would otherwise invariably succumb to their diseases. The understanding and exploitation of the nonspecific alloreactivity of allo-HCT and the graft-versus-tumor effect is contrasted by the genetically engineered precision of CAR T therapy. Historically, those with relapsed and refractory hematologic malignancies have often been considered for allo-HCT, although outcomes vary dramatically and are associated with potential acute and chronic toxicities. Such patients, mainly with B-lymphoid malignancies, may now be offered CAR T therapy. Yet, a lack of prospective data to guide decisions thereafter requires individualized approaches on whether to proceed to allo-HCT or observe. The continued innovations to make CAR T therapy more effective and accessible will continue to alter such approaches, but similar innovations in allo-HCT will likely result in similarly improved clinical outcomes. In this review, we describe the history of the two platforms, dissect the clinical indications emphasizing their intertwining and competitive roles described in trials and practice guidelines, and highlight innovations in which they complement or inform one another.
e19225 Background: IVIG is used to replenish immunoglobulins in HG due to hematologic malignancies (HM) or their treatment (stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CAR-T)), in an effort to reduce the risk of infections. There is limited high-level evidence to support this use, and IVIG supplies are limited with a recent shortage leading to restricted allotments. We report the results of a stewardship program designed to safely reduce IVIG usage. Methods: An IVIG stewardship plan (ISP) was implemented with the following requirements for IVIG administration: IgG level < 400 mg/dL (corrected for paraprotein) for post-ASCT and post-CAR-T patients, or IgG < 400 mg/dL with evidence of a bacterial infection within the last 3 months that required hospitalization or an emergency department encounter for those with HM. We evaluated the amount of IVIG administered, the incidence of infections, and antibiotic administration before and after implementation of an ISP. Results: In the 3 months pre-ISP, HG accounted for 38% (72/188) of total IVIG orders. 86 pts received IVIG for HG in the 3 months pre-ISP. The amount of IVIG given decreased from 1907 g/month pre-ISP to 670 g/month post-ISP; estimated cost savings in IVIG was $57,561/month. The pre-ISP median IgG level prior to dosing of IVIG was 550 (range 40-1189) mg/dL. Compared to pre-ISP, pts who stopped receiving IVIG post-ISP had lower median pre-dose IgG (444, range 93-819 mg/dL, p<0.05), infections/patient-months (14/141 vs 56/255, p<0.001), antibiotic usage (12/47 vs 44/86, p<0.05), and hospitalization rate for infection (4/55 vs 21/86, p<0.05); no deaths occurred. For those receiving IVIG post-ISP, adherence to guidelines was 64%. Compared to pre-ISP, median pre-dose IgG was lower (328, range 51-1011 mg/dL, p<0001), infections/patient-months decreased (27/163 vs 56/255, p<0.001), and antibiotic usage, hospitalization rate for infection, and deaths from infection all remained stable. Conclusions: An ISP for HG led to a dramatic and sustainable decrease in IVIG usage, primarily by selecting out patients who are low risk for infection after discontinuation of IVIG. Such an ISP is replicable and warrants adoption.