P1, N=152, Recruiting, Zhejiang Teruisi Pharmaceutical Inc. | Trial completion date: Nov 2022 --> Dec 2024 | Trial primary completion date: Aug 2022 --> Dec 2023

P1, N=18, Suspended, Mayo Clinic | Trial completion date: Jun 2023 --> Apr 2024 | Recruiting --> Suspended

P1, N=121, Recruiting, Zhejiang Teruisi Pharmaceutical Inc.

In this small study, there was a statistical increase in CD4, CD14, CD68, CD8A, B7-H3, PDL-1, CD19, FOXP3, CD44, and STAT3 protein expression in methylated versus unmethylated GBM tumour core; however, this requires larger cohort validation. Advanced multiplex immunooncological biomarker analysis may be useful in identifying biomarkers for novel immunotherapeutic agents in GBMs.

B7-H3 is an important target for immuno-oncology agents for childhood cancers . Our results provide proof-of-principle for the ability of MGC018 to produce profound antitumor activity in select pediatric solid tumor models in a B7-H3 specific manner.

The incorporation of CD20 monoclonal antibodies (e.g. rituximab) has improved cure rates from 35% to 50% in those with precursor B-cell ALL and from 40 to 80% in those with Burkitt leukemia. More novel antibodies, such as drug conjugates antibodies (e.g. inotuzumab ozogamicin) and bispecific T-cell engagers (e.g. blinatumomab), have shown significant promise in improving outcomes in the relapsed and refractory setting and are currently being studied in the frontline setting, with hopes to further improve long-term outcomes. In this chapter, we will review the role of monoclonal antibodies and how the incorporation of these agents has revolutionized and changed the treatment management of ALL in the frontline setting.

Targeting CD20 with the monoclonal antibody rituximab has improved survival in patients with aggressive B-cell lymphomas, the majority of which are cured with chemoimmunotherapy...The approval of the antibody drug conjugate polatuzumab in combination with chemoimmunotherapy has offered survival benefit to patients who are not candidates for more aggressive approaches and has the potential to change the standard of care for initial management...Herein, promising targets in aggressive lymphoma with the greatest potential for improving outcomes in these patients are discussed. Novel therapies, their toxicities, and their potential role in initial or subsequent treatment are highlighted.

RO7227166, a CD19 targeted 4-1BBL (CD137) costimulatory agonist has shown synergistic anti‑tumor activity when combined with glofitamab in preclinical models (fig 1). The maximum duration of the study for each participant will be up to 24 months in Part I (excluding survival follow-up) and up to 18 months in Part II and Part III. Tumor biopsies and peripheral blood biomarker analyses will be used to demonstrate MoA and proof of concept of an off the shelf flexible combination option providing signals 1 and 2.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis with a median overall survival (OS) of less than 2 years. Obinutuzumab and Venetoclax represents a chemo-free relapse regimen with low toxicity for DLBCL with the ability to induce objective responses in 38.1% of patients including complete remissions. Its potential to serve as a “window-of-opportunity”, relapse- or bridging-treatment in preparation for stem cell or CAR-T cell therapies will be further increased by identification of clinical or biological predictors of response. Supported by a grant from Roche Austria.

In conclusion, our data on the comparison between CD22 and cCD79a expression in CD19 negative relapsed B-ALL patients revealed that, under most circumstances (with 82.5%-91.7% chance), CD22 gating alone could efficiently identify B cells in patients after CD19 CAR-T therapy, which is also a cost-effective and labor-saving strategy for routine practice compared to cCD79a gating. In case of partial or dim CD22 expression, the cCD79a gating is needed.

Conclusions The co-treatment of tafasitamab with RTX demonstrated superiority compared with the respective monotherapies for at least one and up to all three of the modes of action tested (ADCC, ADCP, or direct impact on cell viability) in 9/11 lymphoma cell lines. These data demonstrate that the combination of tafasitamab and RTX mediates increased tumor cell death in vitro via different mechanisms of action and support the clinical evaluation of this antibody combination in patients with DLBCL.

Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion...Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484.

Brentuximab Vedotin, a CD30 antibody-drug conjugate, is not applicable to PTCL subtypes which do not express CD30.2 Broadly targeting pan-T cell markers is predicted to result in extensive T-cell depletion and clinically significant immune deficiency; therefore, a more tumor-specific antigen that primarily targets the malignant T-cell clone is needed...Our results provide proof-of-concept that TCR Vβ family specific T cell-mediated cytolysis is feasible, and informs the development of novel immunotherapies that target TCR Vβ families in T-cell malignancies. Unlike approaches that target pan-T cell antigens, this approach is not expected to cause substantial immune deficiency and could lead to a significant advance in the treatment of T-cell malignancies including PTCL.

In addition, the enhanced dual-modal MRI-fluorescence images can be acquired. In summary, the modular designed BSNP provides an efficient immune-related cancer theranostic strategy, which is of great potential as a simple and universal nanoplatform by combining different antibodies to enhance the cancer theranostic efficacy.

Second-generation TKI and monoclonal antibodies were often approved through expedited regulatory pathways and studied in single-arm trials. This helps to facilitate the approval for earlier use by patients, but is also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events.

The addition of rituximab, a monoclonal antibody against CD20, to upfront therapy has improved survival outcomes for high-risk patients and may allow decreased total chemotherapy in those with low-risk disease...Lastly, trials of small molecule inhibitors targeting cell signaling pathways in NHL subtypes are underway. This article reviews many of the targeted therapies under development that could be considered for future trials in R/R pediatric mature B-NHL.

To overcome impaired antigen presentation, antibody-based cytotoxic strategies, namely antibody-drug conjugates (polatuzumab vedotin and brentuximab vedotin) and bispecific T-cell or NK-cell engagers (blinatumomab, REGN1979, RG6206, and AFM13), have rapidly evolved with promising clinical activity. As additional tools become available for lymphoma treatment, formulation of safe, rational combination strategies to combine them with standard therapy will be of paramount importance. A successful approach to the treatment of lymphoma may require both an optimized anti-tumor immune response as well as effective depletion of malignant lymphoid cells.

Molecular targeted therapies have changed the landscape of treatment strategies for B-NHLs since the approval of rituximab, an anti-CD20 monoclonal antibody, by the US Food and Drug Administration in 1997...However, there are unique toxicities that need to be resolved. It is necessary to find out the toxicity mechanism; optimal treatment strategy for these toxicities; and novel targeted therapies which might potentially overcome the toxicities of previously approved targeted therapies.

Whether one novel agent (inotuzumab, venetoclax, blinatumomab), or combination, is more effective or better tolerated is not known...A phase I study of the combination of venetoclax plus navitoclax (a BCL-2/BCL-XL/BCL-W inhibitor) in combination with chemotherapy for relapsed/refractory pediatric and adult patients (n = 36, with 29 adult and 7 pediatric patients; median age 27 years) deserves mention due to report of excellent tolerability with an impressive ORR of 56% (20/36; 10 = MRD-negative) in a very heavily pretreated population (median 4 prior therapies).32 This combination appears worthy of further development in initial and relapsed settings and highlights the need to continue to evaluate new agents and combinations that may further improve outcomes in newly diagnosed and relapsed disease. persistent high rates of early death and toxicity and infrequent durable remissions (2-year OS ∼20–30%), as reviewed by Gokbuget.14 For instance (Table 1), a recent 4-institution effort in the US enrolled older adults (51–75 years) on a phase 2 study of a chemotherapy regimen derived from the Dana-Farber ALL consortium pediatric-inspired regimen (4-drug induction including asparaginase; clofarabine consolidation), with the goal of early transplant in first CR.15 Among the 30 patients, 20 (67%) achieved CR, 16 (53%) were bridged to transplant, and 52% were alive at 2 years. Grade 3/4 hyperbilirubinemia was frequent (33%), often delayed therapy, and required dose reductions of asparaginase. The largest (n = 268) prospective trial of chemotherapy designed specifically for older adults (modified intensive Berlin-Frankfurt-Munster regimen) was conducted by the German Multicenter ALL (GMALL) cooperative group and reported a CR, early mortality, and 5-year OS rates of 76%, 14%, and 23%, respectively.16 Although certainly there have been incremental improvements in outcomes with the addition of rituximab to chemotherapy in CD20+ B-ALL17, 18 and increasing use of transplantant,19, 20 more effective and safer treatments are needed for older adults with Ph-negative B-ALL for whom there is no standard of care.

P1; Not yet recruiting --> Recruiting

P1; N=20; Not yet recruiting; Sponsor:Hoffmann-La Roche