Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety.

Increased susceptibility to genital herpes in medroxyprogesterone-treated mice may provide a surrogate of increased HIV risk and a preclinical biomarker of topical preexposure prophylaxis safety. We evaluated tenofovir disoproxil fumarate (TDF) in this murine model because an intravaginal ring eluting this drug is being advanced into clinical trials. To avoid the complications of surgically inserting a ring, hydroxyethylcellulose (HEC)-stable formulations of TDF were prepared. One week of twice-daily 0.3% TDF gel was well tolerated and did not result in any increase in HSV-2 susceptibility but protected mice from herpes simplex virus 2 (HSV-2) disease compared to mice treated with the HEC placebo gel. No significant increase in inflammatory cytokines or chemokines in vaginal washes or change in cytokine, chemokine, or mitochondrial gene expression in RNA extracted from genital tract tissue was detected. To further evaluate efficacy, mice were treated with gel once daily beginning 12 h prior to high-dose HSV-2 challenge or 2 h before and after viral challenge (BAT24 dosing). The 0.3% TDF gel provided significant protection compared to the HEC gel following either daily (in 9/10 versus 1/10 mice, P < 0.01) or BAT24 (in 14/20 versus 4/20 mice, P < 0.01) dosing. In contrast, 1% tenofovir (TFV) gel protected only 4/10 mice treated with either regimen. Significant protection was also observed with daily 0.03% TDF compared to HEC. Protection was associated with greater murine cellular permeability of radiolabeled TDF than of TFV. Together, these findings suggest that TDF is safe, may provide substantially greater protection against HSV than TFV, and support the further clinical development of a TDF ring.

Convalescent Plasma for the Treatment of Severe COVID-19 Infection in Cancer Patients.

BACKGROUND: Patients with malignancy are particularly vulnerable to infection with Severe Acute Respiratory Disease-Coronavirus-2 (SARS-CoV-2) given their immunodeficiency secondary to their underlying disease and cancer-directed therapy. We report a case series of patients with cancer who received convalescent plasma, an investigational therapy for severe Coronavirus Disease 2019 (COVID-19). METHODS: Patients with cancer were identified who received convalescent plasma. Enrolled patients had confirmed COVID-19 with severe or life-threatening disease and were transfused with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of ≥ 1:320 dilution. Oxygen requirements and clinical outcomes of interests were captured as well as laboratory parameters at baseline and 3 days after treatment. RESULTS: We identified 24 patients with cancer, 14 of whom had a hematological malignancy, who were treated with convalescent plasma. Fifteen patients (62.5%) were on cancer-directed treatment at the time of COVID-19 infection. After a median of hospital duration of 9 days, 13 patients (54.2%) had been discharged home, 1 patient (4.2%) was still hospitalized, and 10 patients had died (41.7%). Non-intubated patients, particularly those on nasal cannula alone, had favorable outcomes. Three mild febrile non-hemolytic transfusion reactions were observed. C-reactive protein significantly decreased after 3 days of treatment, while other laboratory parameters including ferritin and D-dimer remained unchanged. CONCLUSIONS: Convalescent plasma may be a promising therapy in cancer patients with COVID-19.

Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease.

Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.

Effect of naive and radiolabeled rhTRAIL on the cervical cancer xenografts in mice.

BACKGROUND: There is a need for novel treatments of advanced cervical cancer. We investigated the utility of recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL), a molecule capable of inducing apoptosis in cancer cells, for the therapy of CasKi cervical cancer xenografts in nude mice. RESULTS: CasKi cells proved to be sensitive in vitro to rhTRAIL with an IC50 of 120 ng/ml. (125)I-tagged rhTRAIL specifically accumulated in CasKi tumors in mice with the highest uptake of 9.4% ID/g at 2 h post-injection. Both naive and 200 µCi (188)Re-tagged rhTRAIL administered in the amount of 0.35 mg/kg body weight significantly retarded CasKi tumor growth to the same extent in mice without the side effects of cisplatin chemotherapeutic control. CONCLUSION: rhTRAIL is a promising novel agent for treatment of advanced cervical cancer.

Treatment of experimental pancreatic cancer with 213-Bismuth-labeled chimeric antibody to single-strand DNA.

BACKGROUND: Novel approaches to treatment of pancreatic cancer (PCa) are urgently needed. A chimeric monoclonal antibody (mAb) chTNT3 binds to single-strand DNA (ssDNA) and RNA released from the non-viable cells in fast growing tumors. Here the authors investigated whether radioimmunotherapy (RIT) using chTNT3 mAb radiolabeled with 213-Bismuth ((213)Bi) could be effective in treatment of experimental PCa. METHODS: Two human PCa cell lines, Panc1 and MiaPaCa-2, were used for in vitro experiments. The xenografts in mice were established using MiaPaCa-2 cells. Therapy compared (213)Bi-chTNT3 (700 µCi) to gemcitabine or cisplatin, untreated controls and 'cold' chTNT3. RESULTS: RIT abrogated the tumors growth while tumors in control groups grew aggressively. Chemotherapy was less effective than RIT and toxic to mice while RIT did not have any side effects. CONCLUSIONS: RIT with (213)Bi-chTNT3 was safe and effective in the treatment of experimental PCa in comparison with chemotherapy. This makes α-RIT targeting ssDNA a promising modality for further development.

Complement-dependent cytotoxicity of an antibody to melanin in radioimmunotherapy of metastatic melanoma.

AIM: Novel treatments for metastatic melanoma are urgently needed. MATERIALS & METHODS: We developed radioimmunotherapy of metastatic melanoma using 6D2 monoclonal antibody (mAb) to melanin with encouraging therapeutic results, preclinically and in patients. RESULTS: We observed tumor suppression with the unlabeled 6D2 mAb and investigated its tumoricidal mechanisms. In melanoma tumor-bearing mice, we detected more complement-C3 deposition in the tumors from 188-rhenium-labeled 6D2 mAb-treated mice when compared with untreated controls. 6D2 and isotype-control mAb TEPC caused suppression of tumor growth in A2058 melanoma tumor-bearing mice. Tumors of mice treated with the unlabeled 6D2 mAb were infiltrated with more lymphocytes compared with controls. In vitro antibody-dependent cell-mediated cytotoxicity did not contribute to the tumor-suppressive effect of 6D2 mAb, while 6D2 mAb demonstrated a strong effect on initiating complement-dependent cytotoxicity. CONCLUSION: We concluded that 6D2 mAb mediated complement-dependent cytotoxicity, resulting in killing of the tumor cells and suppression of tumor growth. These observations will help to improve the treatment protocols of radioimmunotherapy, as well as immunotherapy.

Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy.

INTRODUCTION: In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium((188)Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. METHODS: Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi (188)Re-6D2 antibody, saline, unlabeled 6D2 antibody or (188)Re-labeled non-specific IgM. RESULTS: On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P<0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers--chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. CONCLUSIONS: These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5+ and JARID1B+cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.

Compton scattering by internal shields based on melanin-containing mushrooms provides protection of gastrointestinal tract from ionizing radiation.

There is a need for radioprotectors that protect normal tissues from ionizing radiation in patients receiving high doses of radiation and during nuclear emergencies. We investigated the possibility of creating an efficient oral radioprotector based on the natural pigment melanin that would act as an internal shield and protect the tissues via Compton scattering followed by free radical scavenging. CD-1 mice were fed melanin-containing black edible mushrooms Auricularia auricila-judae before 9 Gy total body irradiation. The location of the mushrooms in the body before irradiation was determined by in vivo fluorescent imaging. Black mushrooms protected 80% of mice from the lethal dose, while control mice or those given melanin-devoid mushrooms died from gastrointestinal syndrome. The crypts of mice given black mushrooms showed less apoptosis and more cell division than those in control mice, and their white blood cell and platelet counts were restored at 45 days to preradiation levels. The role of melanin in radioprotection was proven by the fact that mice given white mushrooms supplemented with melanin survived at the same rate as mice given black mushrooms. The ability of melanin-containing mushrooms to provide remarkable protection against radiation suggests that they could be developed into oral radioprotectors.

Novel products of the HUD, HUC, NNP-1 and alpha-internexin genes identified by autologous antibody screening of a pediatric neuroblastoma library.

Autologous serological screening of a cDNA expression library (SEREX) derived from childhood neuroblastoma led to the identification of 10 different antigens, including 6 novel gene products. The novel antigen 018INX was derived from a small open reading frame in a region of alpha-internexin mRNA that was previously described as 3' untranslated region. 018INX thus represents a novel type of tumor antigen. Five novel gene products were derived from NNP-1 (NNP3) and Hu genes (HuC-L, HuD3, HuDY, HuD1pro(c)). As indicated by sequence analysis, these antigens were generated by alternative splicing and/or alternative promoter usage or allelic polymorphism. mRNA expression analyses revealed different tissue restrictions of novel compared to known HuD and NNP-1 transcripts in normal and malignant tissues. The expressions patterns of distinct transcripts indicated potential clinical meanings as diagnostic and/or prognostic tissue markers. When kinetics of serum antibody titres against SEREX-defined antigens were compared to tumor load over time in our patient with neuroblastoma, we found 100-fold increases of anti-Hu and anti-018INX antibody titres preceding the clinical diagnosis of recurrent tumor growth after 2 years. When sera of pediatric patients with cancer (30) and healthy controls (30) were tested for humoral responses to SEREX-defined neuroblastoma antigens, we detected antibodies against all known antigens and NNP3 with low frequencies and titres in control sera, while anti-018INX and anti-Hu antibodies were found in cancer patients only. Our findings indicate that SEREX-defined tumor antigens might provide novel tools for understanding and treatment of this aggressive childhood malignancy.