Redesign of Electrical Installations to Maximize the Use of Photo Voltaic (PV) Cells at the End Use of Consumers in Kuwait

A new idea of redesigning the electrical installations inside residential premises is presented in this paper. The idea is based on having two separate circuits' installations. The first is A.C circuit which can be served by electric grid at standard operating voltage of 230 volts. While the second is D.C circuit being feed directly from the PV cells to meet the demand of all electrical appliances operated at tapered voltage between 12, 24 and 48 volts. The problem of unavailability of PV cell generation during the absence of sun is discussed and solved by introducing a smart interface between the power utility and the consumer having this micro generation PV cells. Smart bidirectional kWh energy meter is used to register the energy consumed by the consumer and the energy being produced by PV cells owned by the consumer himself. In this paper ten years were used to assess the advantages of using this method in Kuwait power systems. Besides the reduction in expansion cost for the power system, a significant release of system capacity was also assessed. Computer software was used to perform the load flow for typical days of the year to show clearly the behavior of the system under these new conditions. As a result of applying this new technique, generator units, transformers, over headlines and underground cables capacity were released. The voltage drop and energy losses through the power system network were reduced as result of reducing the current flow in them. A comparison between continuing to meet the expansion of the system in Kuwait with conventional electric power equipment and using new technique is presented in this paper

Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings

The aim of this study was to evaluate the clinical efficacy as determined by time to progression and response rate (RR) of autologous vitespen (formerly HSPPC-96; Oncophage, Antigenics Inc., New York, NY, USA) with and without interleukin-2 (IL-2; Proleukin: Chiron, Emoryville, CA, USA) in stage IV metastatic renal cell carcinoma (RCC) patients undergoing nephrectomy. Eighty-four patients were enrolled on study, and then underwent nephrectomy and harvest of tumour tissue for use in autologous vaccine manufacture. Initial treatment schedule started approximately 4 weeks after surgery and consisted of six injections: once weekly for 4 weeks, then two injections biweekly (vaccines administered at weeks 1, 2, 3, 4, 6, 8), followed by restaging at or around week 10. Patients who had stable or responsive disease continued to receive vaccine, with four more vaccinations biweekly (at weeks 10, 12, 14, 16). Patients who had progressive disease at week-10 evaluation received four consecutive 5-day-per-week courses of 11 × 106 U of IL-2 subcutaneously (weeks 10, 11, 12, 13), with four doses of vitespen at 2-week intervals (at weeks 10, 12, 14, 16). At the next evaluation (week 18), patients with a complete response received two further cycles of vitespen (with IL-2 if also received during prior cycle) or until vaccine supply was exhausted. Patients with stable disease or partial response repeated their prior cycle of therapy. Disease progressors who had not yet received IL-2 began IL-2 treatment, and progressors who had already received IL-2 came off study. Of 60 evaluable patients, 2 demonstrated complete response (CR), 2 showed partial response (PR), 7 showed stable disease, and 33 patients progressed. Sixteen patients had unconfirmed stable disease. Two patients who progressed on vaccine alone experienced disease stabilisation when IL-2 was added. Treatment with vitespen did not result in a discernable benefit in the majority of patients with metastatic RCC treated in this study. Use in combination with immunoregulatory agents may enhance the efficacy of vitespen

Recent developments in immunotherapy of acute myeloid leukemia

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years. Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results. While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts

Direct Visualization of PR1/HLA-A2 on the Membrane of HLAA2+ CD13+CD33+ Myeloid Leukemia Blasts by a Novel Monoclonal Antibody

Abstract PR1 (VLQELNVTV), the HLA-A2-restricted leukemia-associated antigen (LAA) derived from proteinase 3 (P3) and neutrophil elastase (NE), is targeted by CD8+ T lymphocytes (PR1-CTL) that lyse leukemia but not healthy hematopoietic cells. It is thought that aberrant P3 and NE expression in leukemia causes differential susceptibility to PR1-CTL lysis, perhaps by overexpression of PR1/HLA-A2 on leukemia. Importantly, while PR1-CTL with high affinity T cell receptor (TCR)-αβ are more effective killers of leukemia than low affinity PR1-CTL, they are also deleted by target cells, inducing tolerance and outgrowth of leukemia. Until now, it has not been possible to measure the surface density of PR1/HLA-A2 so critical issues of target specificity and tolerance could be addressed. If PR1 could be directly detected on leukemia, patients might be identified that could benefit from PR1-directed immunotherapy. We sought to develop a monoclonal antibody with specificity for PR1/HLA-A2 to provide direct visualization of the target molecules on leukemia and normal cells. We used two strategies to immunize BALB/c mice: first, PR1-pulsed TAP-deficient T2 cells were injected into the footpads; in the second approach, PR1 refolded with recombinant HLA-A*0201 + β2-microglobulin was injected through intraperitoneal and subcutaneous routes. Draining lymph nodes and spleens was collected and the B cells were fused with myeloma cells to create hybridomas. In the first approach, 1600 hybridoma-derived clones were screened by ELISA with PR1/HLA-A2 monomers, but no specific clones were identified. However, hybridoma clones derived using the second approach resulted in one positive clone from among 950 (designated clone 8F4). Using PR1/HLA-A2 monomers in an ELISA, we confirmed PR1 specificity and showed absence of binding to control peptides including the HLA-A2-restricted peptides pp65 from CMV, FLU peptide from Influenza, and WT1 from Wilm’s tumor antigen. Peptides with amino acid substitutions created at each of the 9 positions in PR1 were used to confirm that modification at P1 from V to A completely abrogated binding by ELISA. 8F4 was identified as IgG2a by standard ELISA using isotype-specific antibodies. Binding affinity of 8F4 was determined to be KD=10 nM by BIACore, compared to KD=162 nM for the common anti-HLA-A*0201 monoclonal antibody BB7.2. The high binding of 8F4 to PR1/HLA-A2 was due largely to its relatively slow off-rate compared to BB7.2. Next, binding specificity was confirmed by FACS using T2 cells pulsed with PR1 and the same control peptides used in the ELISA. To determine whether PR1 could be identified on leukemia, circulating blasts from HLA-A2+ and A2− patients were analyzed with 8F4 directly conjugated to Alexa647 in combination with other surface makers to distinguish blasts. While only 31% of normal monocytes showed minimal 8F4 binding, 73% and 79% of FAB-M1 and FAB-M5 blasts (live CD13+CD33+) bound 8F4 with &amp;gt; 60% staining intensity (MFI) compared to normal monocytes. While PR1 appears to be present on normal cells, AML blasts are preferentially lysed by PR1-CTL but normal monocytes are not. Therefore, PR1-specific TCR-αβ can distinguish small differences in peptide density on normal cells and leukemia. While monoclonal antibodies have been used successfully to treat hematological malignancies, their lack of specificity for tumor results in significant toxicity. It is likely that an antibody against a known LAA+MHC that is expressed only on the leukemia cell membrane would be therapeutically useful without off-target toxicity. Thus, anti-PR1/HLA-A2 antibodies can quantify PR1/HLA-A2 molecules on the leukemia cell surface and can distinguish leukemia from healthy APC.</jats:p

Maintenance Treatment with Guadecitabine (SGI-110) in High Risk MDS and AML Patients after Allogeneic Stem Cell Transplantation

Background: Disease relapse remains to be the one of the major reasons of treatment failures after allogeneic stem cell transplantation (allo-SCT) in AML and MDS patients (pts). SGI-110 is a next generation hypomethylating agent that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. We present interim results of a single arm phase II trial evaluating the efficacy and safety of SGI-110 in AML/MDS pts. to improve transplant outcomes. Methods: In this study, there are 3 treatment cohorts defined by disease status after transplant with different primary outcomes of interest. Cohort 1 includes AML/MDS pts. with morphological relapse after transplant; cohort 2 pts with minimal residual (MRD) and cohort 3 pts with no evidence of disease. As of June 2020, 54 pts have enrolled. Herein, we report the interim analyses of 22 pts treated in cohort 3 and received SGI-110 as post-transplant maintenance while in remission. Other cohorts' results will be reported separately. The maintenance cohort includes high risk AML/MDS pts aged 18-75. High risk MDS is defined as having (1) poor or very poor cytogenetics by revised-IPSS or (2) monosomal karyotype or (3) bone marrow blast count &amp;gt; 5% before transplant; high risk AML as (1) adverse risk group by European LeukemiaNet (ELN) or (2) presence of MRD or active disease at transplant. Therapy-related AML/MDS is included. Pts. are excluded in the presence of (1) active acute graft versus host disease (GvHD), (2) uncontrolled systemic infection, or (3) concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus. The study intervention includes SGI-110 given as 30 mg/m2/day subcutaneously for 5 consecutive days every 28 days until completion of 12 cycles, disease relapse, or experience of unacceptable toxicity. SGI-110 is initiated between 42 to 100 days following allo-SCT if there is adequate engraftment with absolute neutrophil count &amp;gt;/= 1.0 x 109 /L; platelet &amp;gt;/= 50 x 109 /L and no documented evidence of relapse. Treatment delays up to 70 days and dose reductions are allowed per protocol. The primary endpoint for this cohort is relapse-free survival (RFS) time defined as either time to disease progression or death whichever happened first. The maximum planned sample size is 40. Results: As of June 2020, 22 pts were enrolled; M/F, 12/10, median age, 62 (range 18 to74). Of 11 AML pts., ELN risk category was adverse in 8, intermediate in 2 and favorable in 1. Of 11 MDS pts, 6 had poor/very poor and 4 good and 1 intermediate risk cytogenetic abnormalities by revised-IPSS. Of 22, 6 were in complete remission with count recovery at transplant. Median time to initiation of first cycle of maintenance with SGI-110 was 59.5 days (range, 43 to 114 days). So far, 14 pts of 22 were taken off the study; 6 due to disease relapse, 4 completed planned 12 cycles of treatment, 1 lost insurance, 1 withdrew the consent, 1 had travel issues due to COVID19 pandemic and 1 had pulmonary complications unrelated to study drug. Currently, 8 remain to be on the study. Median number of treatment cycles administered have been 4 (range, 1 to 12). Of 22, 7 pts. required the SGI-110 dose to be reduced down to 20 mg/m2/dayX5 days and 1 patient to 20 mg/m2/dayX3 days to be able to continue the treatment. At a median follow-up of 13.1 months for survivors (n=17), RFS and overall survival at 1-year was 66.3% (95% confidence interval (CI)=42% to 82.3%) and 88.9% (95%CI=61.8 to 92.2%) respectively (Figure) During the study, 353 AEs observed with 125 cycles of SGI-110 treatments. Of 353, 287 (81.3%) were attributable to SGI-110 and 133 of 287 (46.3%) were grade 3 or higher in severity. Most of the grade 3 or higher AEs were related with bone marrow suppression; 71 (25%) thrombocytopenia, 64 (22%) neutropenia, 67 (23%) leukopenia and 8 (2%) anemia. Of 22 pts, 15 had grade 4 neutropenia at least once and 8 pts grade 4 thrombocytopenia. There was 18 episodes of infectious AEs and 11 of 18 were grade 3-4. There were no grade 5 AEs observed attributable to study drug. Conclusion: SGI-110 led to frequent grade 3-4 BM suppression in high risk AML/MDS pts when given as maintenance therapy after allo-SCT. However, bone marrow suppression was not associated with increased risk of infection and it was temporary with count recovery. The efficacy of SGI-110 has been promising with 1-year RFS of 66.3%. The study currently is ongoing. Disclosures Oran: Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Champlin:Actinium: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents &amp; Royalties; Johnson and Johnson: Consultancy. OffLabel Disclosure: The abstract presents interim analyses of a clinical trial investigating efficacy and safety of SGI-110 used as maintenance therapy in high risk AML and MDS patients after transplant. </jats:sec

Multiomics profiling and association with molecular and immune features in association with benefits from immunotherapy for patients with previously treated stage IV or recurrent squamous cell lung cancer from the phase III SWOG LungMAP S1400I trial.

9046 Background: Immune checkpoint blockade (ICB) has become a standard pillar of treatment for lung cancer. However, only ̃20% of unselected patients can achieve durable clinical benefits. We performed immunogenomic profiling of tissue specimens from a randomized Phase III trial S1400I on metastatic lung squamous cell carcinoma (SCC) to evaluate if there were factors associated with better prognoses with ICB from single-agent versus combined targeting PD-1/CTLA-4 and evaluate if any differentiated between the treatments. Methods: We utilized FFPE tumor tissue submitted for Lung-MAP screening provided by the SWOG bank. SCC samples from 82 eligible patients treated with combined nivolumab+ipilimumab (N+I) or single agent nivolumab (N) were subjected to multiplex immunofluorescence (mIF, n = 82) and NanoString (ncounter PanCancer Immune Profiling Panel, n = 32). Cell density phenotypes (cells/mm2) were defined using image analysis of staining for cytokeratin, CD3, CD8, granzyme B, CD45RO, FOXP3, PD1, PD-L1, and CD68. Immunogenomic features were associated with response, PFS, and OS derived from data provided by the LungMap team to the CIDC portal. For statistical analyses, non-parametric tests were utilized to assess associations of cell phenotypes versus continuous or categorical variables, and log-rank test analysis was performed to identify cell phenotypes or genes correlated with survival. Results: In both arms higher densities of total CD3+CD45RO+ T cells ( P= 0.041), CD3+PD-1+ T cells ( P= 0.024) and CD3+CD8+PD-1 T cells in stroma ( P= 0.042) and CD3+CD8+GZMB+ T cells in the tumor compartment ( P= 0.011) were positively associated with PFS. In the N+I arm but not in the N arm, higher densities of CD3+CD8+GZMB+ T cells in the tumor compartment were associated with better PFS ( P= 0.015) and higher densities of stroma CD3+CD8-FOXP3+ T cells with worse OS. Spatial analysis showed that the presence of CD8+GZMB+ T cells close to malignant cells (median, ≤19.27 µm) was associated with better PFS ( P= 0.037) in N+I arm and cluster analysis showed low clustering of cells in TMB-high vs. TMB-low tumors (P &lt; 0.01). Gene expression profiling demonstrated that myeloid infiltration, immune recruitment, and inflammation genes were associated with a positive clinical outcome ( P&lt; 0.05). In both arms, BLNK, CD163, FCGR2A were associated with better OS ( P&lt; 0.01), IRF1 and BLNK were associated with increased PFS ( P&lt; 0.01). In the N+I arm but not in the N arm, we observed significantly higher CD45 immune cell scores, including CD8 T cells and neutrophils, in responders versus non-responders. Conclusions: Our findings suggest a potential advantage in PFS and OS with an increased presence of cytotoxic immune cells and genes associated with the recruitment and proliferation of these cell types before therapy. </jats:p

Immune phenotype and response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC).

509 Background: In TNBC patients (pts) receiving NAST, increasing tumor infiltrating lymphocytes (TILs) is associated with higher pathologic complete response (pCR) rates. However, since the presence of TIL do not consistently predict pCR, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Methods: T cell receptor (TCR) sequencing, PD-L1 immunohistochemistry and multiplex immunofluorescence were performed on prospectively collected pre-NAST tumor samples from 98 pts with stage I-III TNBC enrolled in ARTEMIS (NCT: 02276443). TCR clonality was calculated using Shannon’s entropy. PD-L1+ was defined as ≥1% immune cell staining. Response to NAST was defined using the residual cancer burden (RCB) index. Associations between TCR clonality, immune phenotype, and response were examined with the Wilcoxon rank sum test, Spearman’s rank correlation and multivariable logistic regression using stepwise elimination (threshold p &gt; 0.2), as appropriate. Results: The pCR rate was 39% (38/98). pCR was associated with higher TCR clonality (median = 0.2 [in pts with pCR] vs 0.1 [in pts with residual disease], p = 0.05). Notably, the association between pCR and higher TCR clonality was observed in pts with ≥5% TIL (n = 61; p = 0.05) but not in pts with &lt; 5% TIL (n = 37; p = 0.87). Among pts with ≥5% TIL, TCR clonality emerged as the only independent predictor of response in a multivariable model of tumor immune characteristics (odds ratio/0.1 increase in TCR clonality: 3.0, p = 0.021). PD-L1+ status was associated with higher TCR clonality (median = 0.2 [in PD-L1+] vs 0.1 [in PD-L1-], p = 0.004). Higher TCR clonality was associated with higher CD3+ (rho = 0.32, p = 0.0018) and CD3+CD8+ (rho = 0.33, p = 0.0013) infiltration but lower expression of PD-1 on CD3+ (rho = -0.24, p = 0.021) and CD3+CD8+ cells (rho = -0.21, p = 0.037). Conclusions: In TNBC, a more clonal T cell population is associated with an immunologically active microenvironment (higher CD3+ and CD3/8+ T cell; lower PD-1+CD3+ and PD-1+CD3/8+ T cell; PD-L1+) and favorable response to NAST, especially in pts with ≥5% TIL, suggesting a role for deep immune phenotyping in further refining the predictive value of TILs. </jats:p