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Current treatments for lymphoma are plagued by substantial toxicity and the inability to overcome drug resistance, leading to eventual relapse and rationalizing the development of novel, less toxic therapeutics and drug combinations. Histone deacetylase inhibitors (HDACis) are a broad class of epigenetic modulators that have been studied in multiple tumor types, including lymphoma. Currently, HDACis are FDA-approved for treating relapsed T-cell lymphomas and multiple myeloma, with ongoing trials in other lymphomas and solid tumors. As single agents, HDACis frequently elicit toxic side effects and have limited efficacy; therefore, many current treatment strategies focus on combinations to boost efficacy while attempting to minimize toxicity. Fermented wheat germ extract (FWGE) is a complementary agent that has shown efficacy in several malignancies, including lymphoma. Here, we utilize a more potent FWGE derivative, known as fermented wheat germ protein (FWGP), in combination with the HDACi AR42, to assess for enhanced activity. We report increased in vitro killing, cell cycle arrest, and in vivo efficacy for this combination compared to each agent alone with minimal toxicity, suggesting a potentially new, minimally toxic treatment modality for lymphoma.

Immunotherapy has revolutionized cancer therapy. Two recently FDA-approved immunotherapies for B-cell malignancies target CD19, in the form of a Bispecific T-Cell Engager (BiTE) antibody construct or chimeric antigen receptor T (CAR-T) cells. Blinatumomab, an FDA-approved BiTE, binds to CD19 on B cells and to CD3 on T cells, mediating effector-target cell contact and T-cell activation that results in effective elimination of target B cells. Although CD19 is expressed by essentially all B-cell malignancies at clinical presentation, relapses with loss or reduction in CD19 surface expression are increasingly recognized as a cause of treatment failure. Therefore, there is a clear need to develop therapeutics for alternate targets. We have developed a novel BiTE consisting of humanized anti-CD22 and anti-CD3 single chain variable fragments. Target binding of the anti-CD22 and anti-CD3 moieties was confirmed by flow cytometry. CD22-BiTE promoted in vitro cell-mediated cytotoxicity in a dose and effector: target (E:T)-dependent fashion. Additionally, in an established acute lymphoblastic leukemia (ALL) xenograft mouse model, CD22-BiTE demonstrated tumor growth inhibition, comparable to blinatumomab. Further, the combination of blinatumomab and CD22-BiTE yielded increased efficacy in vivo when compared to the single agents. In conclusion, we report here the development of a new BiTE with cytotoxic activity against CD22 +  cells which could represent an alternate or complementary therapeutic option for B-cell malignancies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The state-of-the-art configurations for acoustic-resolution photoacoustic (PA) microscope (AR-PAM) are large in size and expensive, hindering their democratization. While previous research on AR-PAMs introduced a low-cost light source to reduce the cost, few studies have investigated the possibility of optimizing the sensor actuation, particularly for the AR-PAM. Additionally, there is an unmet need to evaluate the image quality deterioration associated with the actuation inaccuracy. A low-cost actuation device is introduced to reduce the system size and cost of the AR-PAM while maintaining the image quality by implementing the advanced beamformers. This work proposes an AR-RAM incorporating the delta configuration actuator adaptable from a low-cost off-the-shelf 3D printer as the sensor actuation device. The image degradation due to the data acquisition positioning inaccuracy is evaluated in the simulation. We further assess the mitigation of potential actuation precision uncertainty through advanced 3D synthetic aperture focusing algorithms represented by the Delay-and-Sum (DAS) with Coherence Factor (DAS+CF) and Delay-Multiply-and-Sum (DMAS) algorithms. The simulation study demonstrated the tolerance of image quality on actuation inaccuracy and the effect of compensating the actuator motion precision error through advanced reconstruction algorithms. With those algorithms, the image quality degradation was suppressed to within 25% with the presence of 0.2 mm motion inaccuracy. The experimental evaluation using phantoms and an ex-vivo sample presented the applicability of low-cost delta configuration actuators for AR-PAMs. The measured full width at half maximum of the 0.2 mm diameter pencil-lead phantom were 0.45 ± 0.06 mm, 0.31 ± 0.04 mm, and 0.35 ± 0.07 mm, by applying the DAS, DAS+CF, and DMAS algorithms, respectively. AR-PAMs with a compact and low-cost delta configuration provide high-quality PA imaging with better accessibility for biomedical applications. The research evaluated the image degradation contributed by the actuation inaccuracy and suggested that the advanced beamformers are capable of suppressing the actuation inaccuracy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ( EGFR )-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance., Methods: A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR -mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination., Results: The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%., Conclusion: Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Caroline E. McCoachHonoraria: Novartis, Genentech, Guardant Health Consulting or Advisory Role: AstraZeneca Speaker’s Bureau: Novartis Research Funding: Novartis, Revolution Medicine Travel, Accommodations, Expenses: Loxo, Eli Lilly, Takeda PharmaceuticalsAiming YuStock and Other Ownership Interests: Johnson & Johnson Patents, Royalties, Other Intellectual Property: Patents: (1) Yu AM, Wang WP, Chen QX, Li MM. Hybrid tRNA/pre-miRNA molecules and methods of use. US Patent No. 10619156, Issue date: April 14, 2020. European Patent No. 3150980, Grant date: May 20, 2020. (2) Yu AM. Method for detection of RNase activity. US Patent No. 10422003. Issue date: September 24, 2019. (3) Yu AM, Jilek JL, Zhang QY, Ho PY, Tu MJ. tRNA/pre-miRNA compositions and methods for treating hepatocellular carcinoma. US Patent Application No. 62/660919, filed on April 20, 2018. (4) Yu AM, Ho PY, Tu MJ, Jilek JL, Zhang QY, Petrek HE. tRNA/pre-miRNA compositions and use in treating cancer. US Patent Application No. 62/674939, filed on May 22, 2018.David R. GandaraHonoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca (I), Guardant Health (I), OncoCyte (I), Amgen, IO Biotech (I), Merck, Roche/Genentech, Boehringer Ingelheim, Inivata, Novartis Research Funding: Roche/Genentech (I), Merck (I), Amgen (I) Travel, Accommodations, Expenses: Boehringer IngelheimJonathan W. RiessConsulting or Advisory Role: Celgene, Medtronic, Spectrum Pharmaceuticals, Loxo, Boehringer Ingelheim, Novartis, Blueprint Medicines, Genentech Research Funding: Merck (I), AstraZeneca/MedImmune (I), Spectrum Pharmaceuticals (I), Boehringer Ingelheim (I), Novartis (I)Tiahong LiConsulting or Advisory Role: Foundation Medicine, Archer Diagnostics, Eisai Research Funding: Pfizer (I), Hengrui Therapeutics (I), Eureka (I), Merck (I), OncoImmune (I)Primo N. LaraConsulting or Advisory Role: Janssen Research Funding: Aragon Pharmaceuticals (I), Janssen Biotech (I), Tracon Pharma (I), Merck (I), Pharmacyclics (I), Incyte (I), Taiho Pharmaceutical (I)Matthew GubensConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, AstraZeneca, Heron, Boehringer Ingelheim, Takeda Pharmaceuticals, BeyondSpring Pharmaceuticals, Inivata Research Funding: Celgene (I), Merck (I), Novartis (I), Roche/Genentech (I), OncoMed (I)Philip C. MackHonoraria: Guardant Health Consulting or Advisory Role: AstraZeneca, Guardant Health, Amgen Research Funding: Boehringer IngelheimKaren KellyHonoraria: Merck Consulting or Advisory Role: Roche/Genentech, Regeneron, AbbVie, EMD Serono, Merck, Pfizer, AstraZeneca, Novartis, Symphogen, Inivata, Bristol Myers Squibb, Takeda Pharmaceuticals, Eli Lilly, Amgen, Genmab, Targeted Oncology, Genentech Research Funding: EMD Serono (I), Genentech (I), AbbVie (I), Five Prime Therapeutics (I), Regeneron (I), Astellas Pharma (I), Tizona Therapeutics, (I) Eli Lilly (I), Novartis (I), Amgen (I) Patents, Royalties, Other Intellectual Property: Author royalties for UpToDate, an evidence-based, peer-reviewed information resource, available via the web, desktop, and PDA Travel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, Merck, Regeneron, Eli Lilly, AbbVie, EMD Serono No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Current standard workflows of ultrasound (US)-guided needle insertion require physicians to use their both hands: holding the US probe to locate interested areas with the non-dominant hand and the needle with the dominant hand. This is due to the separation of functionalities for localization and needle insertion. This requirement does not only make the procedure cumbersome, but also limits the reliability of guidance given that the positional relationship between the needle and US images is unknown and interpreted with their experience and assumption. Although the US-guided needle insertion may be assisted through navigation systems, recovery of the positional relationship between the needle and US images requires the usage of external tracking systems and image-based tracking algorisms that may involve the registration inaccuracy. Therefore, there is an unmet need for the solution that provides a simple and intuitive needle localization and insertion to improve the conventional US-guided procedure. In this work, we propose a new device concept solution based on the ring-arrayed forward-viewing (RAF) ultrasound imaging system. The proposed system is comprised with ring-arrayed transducers and an open whole inside the ring where the needle can be inserted. The ring array provides forward-viewing US images, where the needle path is always maintained at the center of the reconstructed image without requiring any registration. As the proof of concept, we designed single-circle ring-arrayed configurations with different radiuses and visualized point targets using the forward-viewing US imaging through simulations and phantom experiments. The results demonstrated the successful target visualization and indicates the ring-arrayed US imaging has a potential to improve the US-guided needle insertion procedure to be simpler and more intuitive.

EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885-96. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine., Methods: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo. The effects of ospemifene (OSP) on the immune response to a peptide cancer vaccine (PV) were evaluated after chronic [control (n = 22); OSP 50 mg/kg (n = 16); PV (n = 6); OSP+PV (n = 11)], intermittent [control (n = 10); OSP 10 and 50 mg/kg (n = 11); PV (n = 11); combination treatment (n = 11 each dose)] and pretreatment [control; OSP 100 mg/kg; PV 100 μg; combination treatment (n = 8 all groups)] ospemifene oral dosing schedules in a total of 317 mixed-sex tumor-bearing and nontumor-bearing mice., Results: The results showed that ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigen-specific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigen-induced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively., Conclusions: Taken together, ospemifene's dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies.

Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy., (©2015 American Association for Cancer Research.)

The goals of the present study were to define the effects of simultaneous cisplatin/tecemotide therapy on tumor development in a human mucin 1 (MUC1) transgenic lung cancer mouse model and to examine the effects of radiotherapy (RTX) on splenocytes, serum cytokines, and immune response to tecemotide. Two hundred twenty-six human MUC1 transgenic C57BL/6 mice were used in five studies designed to assess (i) serum cytokine and immune responses following four weekly 10-μg doses of tecemotide; (ii) the effects of simultaneous administration of cisplatin (2.5 mg/kg × 2 doses/cycle × 4 cycles) and tecemotide (2 cycles × 8 weekly 10-μg doses/cycle) therapy on tumor development, serum cytokines, and immune response; (iii) the dose-response effects of RTX on lymphocyte counts 16 hours following doses of 2 to 8 Gy; (iv) the time course of lymphocyte recovery from 16 hours to 20 days following 8-Gy RTX; and (v) the effects of simultaneous administration of RTX (8 Gy) and tecemotide on the immune response to tecemotide (four weekly 10-μg doses). Serum cytokines were analyzed by multiplex immunoassay, IFNγ immune responses by enzyme-linked immunosorbent spot (ELISpot), and lung tumor foci by lung whole mounts. Simultaneous cisplatin/tecemotide therapy resulted in significant and additive reduction in lung tumor foci compared with control mice, with significantly elevated serum IFNγ levels and specific IFNγ immune responses observed in both tecemotide and tecemotide + cisplatin-treated mice. Finally, neither cisplatin nor radiation interfered with the immune response to tecemotide., (©2014 American Association for Cancer Research.)

A preclinical model of invasive bladder cancer was developed in human mucin 1 (MUC1) transgenic (MUC1.Tg) mice for the purpose of evaluating immunotherapy and/or cytotoxic chemotherapy. To induce bladder cancer, C57BL/6 mice (MUC1.Tg and wild type) were treated orally with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) at 3.0 mg/day, 5 days/week for 12 weeks. To assess the effects of OH-BBN on serum cytokine profile during tumor development, whole blood was collected via submandibular bleeds prior to treatment and every four weeks. In addition, a MUC1-targeted peptide vaccine and placebo were administered to groups of mice weekly for eight weeks. Multiplex fluorometric microbead immunoanalyses of serum cytokines during tumor development and following vaccination were performed. At termination, interferon gamma (IFN-γ)/interleukin-4 (IL-4) ELISpot analysis for MUC1 specific T-cell immune response and histopathological evaluations of tumor type and grade were performed. The results showed that: (1) the incidence of bladder cancer in both MUC1.Tg and wild type mice was 67%; (2) transitional cell carcinomas (TCC) developed at a 2:1 ratio compared to squamous cell carcinomas (SCC); (3) inflammatory cytokines increased with time during tumor development; and (4) administration of the peptide vaccine induces a Th1-polarized serum cytokine profile and a MUC1 specific T-cell response. All tumors in MUC1.Tg mice were positive for MUC1 expression, and half of all tumors in MUC1.Tg and wild type mice were invasive. In conclusion, using a team approach through the coordination of the efforts of pharmacologists, immunologists, pathologists and molecular biologists, we have developed an immune intact transgenic mouse model of bladder cancer that expresses hMUC1.

Background: L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity., Methods: A chemically-induced lung tumor model was developed in hMUC1.Tg C57BL/6 mice by administering 10 weekly 0.75-mg/g doses of the chemical carcinogen urethane by intraperitoneal injection. Serum cytokines associated with Th1/Th2 polarization and inflammation were measured by multiplex cytokine assay during tumorigenesis. Antitumor activity of L-BLP25 (10 μg) with CPA (100 mg/kg) pretreatment was evaluated following either one or two eight-week cycles of treatment by preparing lung whole mounts and counting tumor foci, and assessing IFN-γ production by ELISpot assay., Results: During the carcinogenesis phase, no detectable Th1- or Th2-associated cytokine responses were observed, but levels of pro-inflammatory cytokines were increased with distinctive kinetics. A single cycle of L-BLP25 consisting of eight weekly doses was ineffective, whereas adding a second cycle given during tumor progression showed a significant reduction in the incidence of tumor foci. Administering two cycles of L-BLP25 induced Th1 cytokines IL-12, IL-2 and IFNγ at 24 h after the last dose, while Th2 and inflammatory cytokines were elevated to a lesser extent., Conclusions: Urethane-induced lung tumors in hMUC1.Tg mice can be used as a model to assess the efficacy of the MUC1 antigen-specific cancer immunotherapeutic agent L-BLP25. The results indicate that the antitumor response to L-BLP25 requires at least two cycles and pre-treatment with CPA. In addition, monitoring pro-inflammatory serum cytokines may be useful as a biomarker of L-BLP25 response. Taken together, the preclinical lung tumor model can be utilized for determining effective combinations of L-BLP25 with chemotherapy and/or other immunotherapies.