Pharmacodynamic changes in tumor and immune cells drive iberdomide's clinical mechanisms of activity in relapsed and refractory multiple myeloma

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity

DNA prime Listeria boost induces a cellular immune response to SIV antigens in the rhesus macaque model that is capable of limited suppression of SIV239 viral replication

AbstractDNA vaccines and recombinant Listeria monocytogenes that express and secrete SIV Gag and Env antigens were combined in a nonhuman primate prime-boost immunogenicity study followed by a challenge with SIV239. We report that recombinant DNA vaccine delivered intramuscularly, and recombinant L. monocytogenes delivered orally each individually have the ability to induce CD8+ and CD4+ T cell immune responses in a nonhuman primate. Four rhesus monkeys were immunized at weeks 0, 4, 8, and 12 with the pCSIVgag and pCSIVenv DNA plasmids and boosted with SIV expressing L. monocytogenes vaccines at weeks 16, 20, and 28. Four rhesus monkeys received only the L. monocytogenes vaccines at weeks 16, 20, and 28. A final group of monkeys served as a control group. Blood samples were taken before vaccination and 2 weeks post each injection and analyzed by ELISPOT for CD4+ and CD8+ T cell responses. Moderate vaccine induced SIV-specific cellular immune responses were observed following immunization with either DNA or L. monocytogenes vectors. However, the SIV antigen-specific immune responses were significantly increased when Rhesus macaques were primed with SIV DNA vaccines and boosted with the SIV expressing L. monocytogenes vectors. In addition, the combined vaccine was able to impact SIV239 viral replication following an intrarectal challenge. This study demonstrates for the first time that oral L. monocytogenes can induce a cellular immune response in a nonhuman primate and is able to enhance the efficacy of a DNA vaccine as well as provide modest protection against SIV239 challenge

Interaction between polymorphisms of the Human Leukocyte Antigen and HPV-16 Variants on the risk of invasive cervical cancer

<p>Abstract</p> <p>Background</p> <p>Persistent infection with oncogenic types of human papillomavirus (HPV) is the major risk factor for invasive cervical cancer (ICC), and non-European variants of HPV-16 are associated with an increased risk of persistence and ICC. HLA class II polymorphisms are also associated with genetic susceptibility to ICC. Our aim is to verify if these associations are influenced by HPV-16 variability.</p> <p>Methods</p> <p>We characterized HPV-16 variants by PCR in 107 ICC cases, which were typed for <it>HLA-DQA1</it>, <it>DRB1 </it>and <it>DQB1 </it>genes and compared to 257 controls. We measured the magnitude of associations by logistic regression analysis.</p> <p>Results</p> <p>European (E), Asian-American (AA) and African (Af) variants were identified. Here we show that inverse association between <it>DQB1*05 </it>(adjusted odds ratio [OR] = 0.66; 95% confidence interval [CI]: 0.39–1.12]) and HPV-16 positive ICC in our previous report was mostly attributable to AA variant carriers (OR = 0.27; 95%CI: 0.10–0.75). We observed similar proportions of <it>HLA DRB1*1302 </it>carriers in E-P positive cases and controls, but interestingly, this allele was not found in AA cases (p = 0.03, Fisher exact test). A positive association with <it>DRB1*15 </it>was observed in both groups of women harboring either E (OR = 2.99; 95% CI: 1.13–7.86) or AA variants (OR = 2.34; 95% CI: 1.00–5.46). There was an inverse association between <it>DRB1*04 </it>and ICC among women with HPV-16 carrying the 350T [83L] single nucleotide polymorphism in the <it>E6 </it>gene (OR = 0.27; 95% CI: 0.08–0.96). An inverse association between <it>DQB1*05 </it>and cases carrying 350G (83V) variants was also found (OR = 0.37; 95% CI: 0.15–0.89).</p> <p>Conclusion</p> <p>Our results suggest that the association between HLA polymorphism and risk of ICC might be influenced by the distribution of HPV-16 variants.</p

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Human papillomavirus infections and cervical neoplasia: Effect of HLA-DRB1 and -DQB1 gene polymorphism and lymphoproliferative responses against viral peptides

Infecção persistente por tipos oncogênicos de papilomavírus humano (HPV) é considerada como o principal fator de risco para desenvolvimento de carcinoma invasivo do colo uterino (CCU) e de lesões intraepiteliais cervicais (SIL). Fatores genéticos do hospedeiro, como o polimorfismos de genes HLA (human leukocyte antigen), também têm sido implicados na suscetibilidade a estas patologias e à infecção por (HPV), como observado em diversos estudos caso-controle. Neste estudo investigou-se em uma coorte de mulheres (Ludwig-McGill cohort) se a variabilidade dos genes HLA-DRB1 e -DQB1 influenciam na história natural das infecções por HPV e no risco de SIL. A tipificação de DRB1 e DQB1 foi realizada em 620 amostras provenientes de um estudo epidemiológico prospectivo. A positividade para HPV foi testada em amostras da mesma paciente coletadas a cada 4 meses, obtidos durante o primeiro ano de seguimento, enquanto os resultados de citologia perfazem os 2 primeiros anos de seguimento. Infecções persistentes de curta ou longa duração foram definidas como 2 e 3 resultados consecutivos positivos para o mesmo tipo de HPV, respectivamente. As associações foram estimadas através de razões de chance e intervalos de confiança de 95%, ajustadas para potenciais fatores de confusão. Os resultados obtidos indicam que a prevalência da infecção por HPV e o risco de persistência variam dependendo do haplótipo HLA. O haplótipo DRB1*0301-DQB1*0201 mostrou-se protetor contra a infecção por HPV, e DRB1*1102-DQB1 *0301 contra infecções persistentes. Já os haplótipos DRB1*1601-DQB1*0502 e DRB1 *0807-DQB1*0402 foram fatores de risco para infecções persistentes por HPV. Não foi observada uma forte concordância entre risco de infecção por HPV e risco de SIL associados a determinado HLA, em parte porque o número de pacientes com SIL foi um fator limitante neste estudo. Um risco aumentado de SIL, independente da infecção por HPV, foi associado com DRB1*0301 e DR12. Portadoras de DR4 e DQB1*0601 tiveram uma maior probabilidade de desenvolver SIL e HSIL, respectivamente. Uma associação negativa entre o alelo DQB1*0301 e HSIL foi verificada. Análise do dimorfismo na posição 86 da cadeia &#946; de HLA-DR mostrou que valina nesta posição tem um efeito protetor para prevalência e persistência de infecção por HPV, e maior risco de SIL no grupo com infecções transitórias por HPV. Em outra análise, investigamos a distribuição de grupos alélicos de DRB1 em uma série independente de amostras provenientes de pacientes com CCU. Observamos um risco diminuído de desenvolvimento de CCU associado a DR3. Por outro lado, DR4 e DR8/12 mostraram-se fatores de risco para o CCU nesta população. Estes resultados sugerem que o polimorfismo de HLA desempenha um papel na história natural das infecções por HPV, SIL e CCU. Também analisamos respostas linfoproliferativas em pacientes com CCU, contra peptídeos derivados de E6 e E7 de HPV16. As respostas positivas foram mais freqüentes contra peptídeos de E6 do que E7. Não observamos resposta contra um peptídeo ou região em particular. Parte desta diversidade nas respostas linfoproliferativas pode ser relacionada com o polimorfismo de genes HLA e seu papel na seleção de epítopos.Persistent infection with oncogenic human papillomavirus (HPV) is the major risk factor for the development of malignant lesions in the uterine cervix. Host factors have also been implicated in the pathogenesis of these diseases. Associations between human leukocyte antigen (HLA) polymorphisms and cervical cancer, precursor lesions or HPV infections have been reported by case-control studies in several populations. This study investigated through cohort analysis if human leukocyte antigen (HLA)-DRB1 and DQB1 variability is related to human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) prevalence and persistence. HLA-DRB1 and DQB1 genes were typed in 620 samples from the Ludwig-McGill cohort. HPV positivity was tested in specimens collected every 4 months during the first year of follow-up. Persistent and long-term infections were defined as at least 2 or 3 consecutive positive results for the same HPV type, respectively. Analysis of SIL included data obtained during the two first years of follow-up. The magnitudes of associations were estimated by unconditional logistic regression analysis adjusted for potential confounders. Certain HLA alleles and haplotypes were associated with HPV either HPV prevalence or persistence. The DRB1*0301-DQB1*0201 haplotype was associated with a lower risk for HPV infection and DRB1*1102-DQB1*0301 for HPV persistence. DRB1*1601-DQB1*0502 and DRB1*0807-DQB1*0402 were associated with a increased risk for persistent HPV infection. It was not observed a strong concordance between the associations verified for HPV prevalence/persistence and SIL, possibly due to the limited number of SIL specimens. A higher risk for SIL, independent of HPV infection, was observed for DRB1*0301 and DR12. DR4 and DQB1*0601 carriers showed a higher frequency of SIL and HSIL, respectively. A negative association between DQB1*0301 and HSIL was verified. Valine at position 86 of the DR&#946; chain was associated with reduced risks of HPV positivity and persistence, as compared to glycine carriers. However, valine carriers had a higher risk of SIL if transiently infected by HPV. We also analyzed an independent sample of patients with invasive cervical, and a protective effect was observed for DR3. On the other hand, DR4 and DR8/12 were associated with a higher risk for cervical cancer in this population. Our results suggest that HLA class II polymorphisms and pocket 1 profile are involved in clearance and maintenance of HPV infection and the risk of SIL and CCU, consistent with the hypothesis that genetic background is important in the natural history of HPV infections and associated lesions. We also analyzed lymphoproliferative responses against HPV16 E6 and E7 peptides, in patients with invasive cervical cancer. Lymphoproliferative responses were more frequent for E6 peptides than for E7 peptides. The responses were not restricted to a particular peptide, which is expected based on HLA variability observed among patients

Human papillomavirus infections and cervical neoplasia: Effect of HLA-DRB1 and -DQB1 gene polymorphism and lymphoproliferative responses against viral peptides

Infecção persistente por tipos oncogênicos de papilomavírus humano (HPV) é considerada como o principal fator de risco para desenvolvimento de carcinoma invasivo do colo uterino (CCU) e de lesões intraepiteliais cervicais (SIL). Fatores genéticos do hospedeiro, como o polimorfismos de genes HLA (human leukocyte antigen), também têm sido implicados na suscetibilidade a estas patologias e à infecção por (HPV), como observado em diversos estudos caso-controle. Neste estudo investigou-se em uma coorte de mulheres (Ludwig-McGill cohort) se a variabilidade dos genes HLA-DRB1 e -DQB1 influenciam na história natural das infecções por HPV e no risco de SIL. A tipificação de DRB1 e DQB1 foi realizada em 620 amostras provenientes de um estudo epidemiológico prospectivo. A positividade para HPV foi testada em amostras da mesma paciente coletadas a cada 4 meses, obtidos durante o primeiro ano de seguimento, enquanto os resultados de citologia perfazem os 2 primeiros anos de seguimento. Infecções persistentes de curta ou longa duração foram definidas como 2 e 3 resultados consecutivos positivos para o mesmo tipo de HPV, respectivamente. As associações foram estimadas através de razões de chance e intervalos de confiança de 95%, ajustadas para potenciais fatores de confusão. Os resultados obtidos indicam que a prevalência da infecção por HPV e o risco de persistência variam dependendo do haplótipo HLA. O haplótipo DRB1*0301-DQB1*0201 mostrou-se protetor contra a infecção por HPV, e DRB1*1102-DQB1 *0301 contra infecções persistentes. Já os haplótipos DRB1*1601-DQB1*0502 e DRB1 *0807-DQB1*0402 foram fatores de risco para infecções persistentes por HPV. Não foi observada uma forte concordância entre risco de infecção por HPV e risco de SIL associados a determinado HLA, em parte porque o número de pacientes com SIL foi um fator limitante neste estudo. Um risco aumentado de SIL, independente da infecção por HPV, foi associado com DRB1*0301 e DR12. Portadoras de DR4 e DQB1*0601 tiveram uma maior probabilidade de desenvolver SIL e HSIL, respectivamente. Uma associação negativa entre o alelo DQB1*0301 e HSIL foi verificada. Análise do dimorfismo na posição 86 da cadeia &#946; de HLA-DR mostrou que valina nesta posição tem um efeito protetor para prevalência e persistência de infecção por HPV, e maior risco de SIL no grupo com infecções transitórias por HPV. Em outra análise, investigamos a distribuição de grupos alélicos de DRB1 em uma série independente de amostras provenientes de pacientes com CCU. Observamos um risco diminuído de desenvolvimento de CCU associado a DR3. Por outro lado, DR4 e DR8/12 mostraram-se fatores de risco para o CCU nesta população. Estes resultados sugerem que o polimorfismo de HLA desempenha um papel na história natural das infecções por HPV, SIL e CCU. Também analisamos respostas linfoproliferativas em pacientes com CCU, contra peptídeos derivados de E6 e E7 de HPV16. As respostas positivas foram mais freqüentes contra peptídeos de E6 do que E7. Não observamos resposta contra um peptídeo ou região em particular. Parte desta diversidade nas respostas linfoproliferativas pode ser relacionada com o polimorfismo de genes HLA e seu papel na seleção de epítopos.Persistent infection with oncogenic human papillomavirus (HPV) is the major risk factor for the development of malignant lesions in the uterine cervix. Host factors have also been implicated in the pathogenesis of these diseases. Associations between human leukocyte antigen (HLA) polymorphisms and cervical cancer, precursor lesions or HPV infections have been reported by case-control studies in several populations. This study investigated through cohort analysis if human leukocyte antigen (HLA)-DRB1 and DQB1 variability is related to human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) prevalence and persistence. HLA-DRB1 and DQB1 genes were typed in 620 samples from the Ludwig-McGill cohort. HPV positivity was tested in specimens collected every 4 months during the first year of follow-up. Persistent and long-term infections were defined as at least 2 or 3 consecutive positive results for the same HPV type, respectively. Analysis of SIL included data obtained during the two first years of follow-up. The magnitudes of associations were estimated by unconditional logistic regression analysis adjusted for potential confounders. Certain HLA alleles and haplotypes were associated with HPV either HPV prevalence or persistence. The DRB1*0301-DQB1*0201 haplotype was associated with a lower risk for HPV infection and DRB1*1102-DQB1*0301 for HPV persistence. DRB1*1601-DQB1*0502 and DRB1*0807-DQB1*0402 were associated with a increased risk for persistent HPV infection. It was not observed a strong concordance between the associations verified for HPV prevalence/persistence and SIL, possibly due to the limited number of SIL specimens. A higher risk for SIL, independent of HPV infection, was observed for DRB1*0301 and DR12. DR4 and DQB1*0601 carriers showed a higher frequency of SIL and HSIL, respectively. A negative association between DQB1*0301 and HSIL was verified. Valine at position 86 of the DR&#946; chain was associated with reduced risks of HPV positivity and persistence, as compared to glycine carriers. However, valine carriers had a higher risk of SIL if transiently infected by HPV. We also analyzed an independent sample of patients with invasive cervical, and a protective effect was observed for DR3. On the other hand, DR4 and DR8/12 were associated with a higher risk for cervical cancer in this population. Our results suggest that HLA class II polymorphisms and pocket 1 profile are involved in clearance and maintenance of HPV infection and the risk of SIL and CCU, consistent with the hypothesis that genetic background is important in the natural history of HPV infections and associated lesions. We also analyzed lymphoproliferative responses against HPV16 E6 and E7 peptides, in patients with invasive cervical cancer. Lymphoproliferative responses were more frequent for E6 peptides than for E7 peptides. The responses were not restricted to a particular peptide, which is expected based on HLA variability observed among patients

Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy▿

Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted strain that expresses the human prostate-specific antigen (PSA) using an antibiotic resistance marker-free plasmid (the dal dat ΔactA 142 strain expressing PSA). Despite limited in vivo survival, the dal dat ΔactA 142 strain was able to elicit efficient immune responses required for tumor clearance. Our results showed that immunization of mice with the dal dat ΔactA 142 strain caused the regression of the tumors established by the prostate adenocarcinoma cell line expressing PSA. An evaluation of immunologic potency indicated that the dal dat ΔactA 142 strain elicits a high frequency of PSA-specific immune responses. Interestingly, immunization with the dal dat ΔactA 142 strain induced significant infiltration of PSA-specific T cells in the intratumoral milieu. Collectively, our data suggest that the dal dat ΔactA 142 strain is a safe and potent vector for clinical use and that this platform may be further exploited as a potential candidate to express other single or multiple antigens for cancer immunotherapy