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Background: Blinatumomab is a CD19 BiTE (bispecific T‐cell engager) immuno‐oncology therapy that mediates the lysis of cells expressing CD19. Methods: A pooled analysis of long‐term follow‐up data from 2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome–negative, relapsed/refractory B‐cell precursor acute lymphoblastic leukemia was conducted. Results: A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval [CI], 5.5‐8.5 months); the median follow‐up time for OS was 36.0 months (range, 0.3‐60.8 months). The median relapse‐free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2‐10.0 months); the median follow‐up time for RFS was 35.0 months (range, 9.5‐59.5 months). OS and RFS plateaued with 3‐year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3‐year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3‐30.0 months) with a 3‐year survival rate of 37.2%. Conclusions: These data suggest that long‐term survival is possible after blinatumomab therapy. Lay Summary: Immuno‐oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells.This study combined follow‐up data from 2 blinatumomab‐related clinical trials to evaluate long‐term survival in patients with relapsed and/or refractory B‐cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes.Among patients who achieved a deep response with blinatumomab, one‐third lived 3 years or longer. These findings suggest that long‐term survival is possible after treatment with blinatumomab. Patients achieving remission after blinatumomab can have a durable response. The survival plateau indicates a high probability of a cure in those patients responding to blinatumomab and alive after 3 years. [ABSTRACT FROM AUTHOR]

Adoptive T-cell immunotherapies, including chimeric antigen receptor-modified T-cells (CAR-T cells), have revolutionized cancer treatment, especially for hematologic malignancies. Clinical success of CAR-T cell monotherapy in solid tumors however, has been only modest. Oncolytic viruses provide direct cancer cell lysis, stimulate systemic immune responses, and have the capacity to provide therapeutic transgenes. Oncolytic virotherapy has shown great promise in many preclinical solid tumor models and the first oncolytic virus has been approved by the FDA for the treatment of advanced melanoma. As monotherapies for solid tumors, oncolytic virotherapy provides only moderate anti-tumor effects. However, due to their complementary modes of action, oncolytic virus and T-cell therapies can be combined to overcome the inherent limitations of each agent. This review focuses on the aspects of oncolytic viruses that enable them to synergize with adoptive T-cell immunotherapies to enhance anti-tumor effects for solid tumors.

With the current biotherapeutic market dominated by antibody molecules, bispecific antibodies represent a key component of the next-generation of antibody therapy. Bispecific antibodies can target two different antigens at the same time, such as simultaneously binding tumor cell receptors and recruiting cytotoxic immune cells. Structural diversity has been fast-growing in the bispecific antibody field, creating a plethora of novel bispecific antibody scaffolds, which provide great functional variety. Two common formats of bispecific antibodies on the market are the single-chain variable fragment (scFv)-based (no Fc fragment) antibody and the full-length IgG-like asymmetric antibody. Unlike the conventional monoclonal antibodies, great production challenges with respect to the quantity, quality, and stability of bispecific antibodies have hampered their wider clinical application and acceptance. In this review, we focus on these two major bispecific types and describe recent advances in the design, production, and quality of these molecules, which will enable this important class of biologics to reach their therapeutic potential.

The recent clinical approval of different Bi-specific antibodies (BsAbs) has revealed the great therapeutic potential of this novel class of biologicals. For example, the bispecific T-cell engager (BiTE), Blinatumomab, demonstrated the unique capacity of BsAbs to link T-cells with tumor cells, inducing targeted tumor cell removal. Additionally, Amivantamab, recognizing the EGFR and cMet in cis, revealed a substantial improvement of therapeutic efficacy by concomitantly targeting two tumor antigens. Cis-targeting BsAbs furthermore allow discerning cell populations which concurrently express two antigens, for which each antigen expression pattern in itself might not be selective. In this way, BsAbs harbor the great prospect of being more specific and showing fewer side effects than monoclonal antibodies. Nevertheless, BsAbs have also faced major obstacles, for instance, in ensuring reliable assembly and clinical-grade purification. In this review, we summarize the different available antibody platforms currently used for the generation of IgG-like and non-IgG-like BsAbs and explain which approaches have been used to assemble those BsAbs which are currently approved for clinical application. By focusing on the example of regulatory T-cells (Tregs) and the different, ongoing approaches to develop BsAbs specifically targeting Tregs within the tumor microenvironment, our review highlights the huge potential as well as the pitfalls BsAb face in order to emerge as one of the most effective therapeutic biologicals targeting desired cell populations in a highly selective way. Such BsAb may improve treatment efficacy and reduce side effects, thereby opening novel treatment opportunities for a range of different diseases, such as cancer or autoimmune diseases., Competing Interests: Disclosure statement The authors declare no competing interests. Figures created by BioRender., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence. [ABSTRACT FROM AUTHOR]

With the current biotherapeutic market dominated by antibody molecules, bispecific antibodies represent a key component of the next-generation of antibody therapy. Bispecific antibodies can target two different antigens at the same time, such as simultaneously binding tumor cell receptors and recruiting cytotoxic immune cells. Structural diversity has been fast-growing in the bispecific antibody field, creating a plethora of novel bispecific antibody scaffolds, which provide great functional variety. Two common formats of bispecific antibodies on the market are the single-chain variable fragment (scFv)-based (no Fc fragment) antibody and the full-length IgG-like asymmetric antibody. Unlike the conventional monoclonal antibodies, great production challenges with respect to the quantity, quality, and stability of bispecific antibodies have hampered their wider clinical application and acceptance. In this review, we focus on these two major bispecific types and describe recent advances in the design, production, and quality of these molecules, which will enable this important class of biologics to reach their therapeutic potential. [ABSTRACT FROM AUTHOR]