An important difference between testing for primary activity and safety is that, in the former, what to look for is defined; in safety testing it is not . For parameter estimation, we assume a fixed dose of 108 cells, consistent with median dose used in this study and other clinical trials of Kymriah. 9, 20 (2018). 115, 11161129 (2018). Logistic regression with respect to the tumor burden (d), Cmax (e) or the quotient of Cmax and tumor burden (f) reveals how each predicts response (blue curve indicates model estimate with 95% confidence intervals). Some will work as consultants in their sub-specialty interest. Securing one of these jobs, however, can be a challenge. b, A bivariate classifier based on calculated T memory (CD8+CD45ROCD27+) and T exhausted (CD8+PD1+) cell frequencies from Bai et al.34. The median pharmacokinetics and population variance of Yescarta are similar to Kyrmiah (Supplementary Fig. Tumor cells express B cell antigen (BA), which stimulates T cell proliferation and differentiation and inhibits the formation of T memory cells. Chimeric antigen receptor T cell (CAR-T) expansion and persistence vary widely among patients and predict both efficacy and toxicity. We again used PSO to estimate model parameters characterizing the pharmacokinetics and tumor dynamics (Fig. YESCARTA (FDA, 2017); https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/BLA-Clinical-Review-Memorandum--October-5--2017---YESCARTA.pdf, Kaushal, M. & Natrajan, K. BLA Clinical Review Memorandum. 11). b, We fit the model to published pharmacokinetics/pharmacodynamics profiles separated by response category (CR/PR/NR) from Fraietta et al.18 using PSO. However, the magnitude of differences between the populations cannot be fully explained by this hypothesis. Cell population gene sets derived from literature. Most CD8+ cells in all three datasets are classified as T effector memory (Tem) or T exhausted (Tex), but there are no consistent differences in composition by response category (Supplementary Fig. However, the mechanisms underlying clinical outcomes and patient variability are poorly defined. 66, 427438 (2012). Gillespie, M. et al. and JavaScript. Boer, R. J. D. & Perelson, A. S. Towards a general function describing T cell proliferation. The best clinical pharmacology drug development services are built for flexibility. Individuals who prepare and dispense . As nouns the difference between pharmacology and pharmacodynamics is that pharmacology is (medicine) the science that studies the effects of chemical compounds on living animals, especially the science of the manufacture, use and effects of medicinal drugs while pharmacodynamics is (pharmacology) the branch of pharmacology that studies the effects and modes of action of drugs upon the body. Clinical Pharmacology & Therapeutics; CPT: Pharmacometrics & Systems Pharmacology; Clinical and Translational Science; ASCPT.org; . As a control, we first assessed differences between cells annotated as exhausted versus non-exhausted. N. Engl. . However, if the infection fails to resolve, chronic antigen stimulation leads to T cell exhaustion, wherein remnant T cells lose the ability to produce cytokines, kill target cells or proliferate in response to antigen16,17. Clinical pharmacology encompasses all aspects of the relationship between drugs and humans. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. J. Theor. Whether it is your first-in-human study, an exploratory biomarker study or a study needed for your NDA package, Labcorp scientists and clinicians carefully evaluate drug safety, tolerability and pharmacokinetics. For model fitting, we assume initial tumor burden as 1010 cells and linear scaling between tumor burden and reported soluble BCMA. CAR-T cells from NR patients show heightened p53 (ref. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Deconvolution of clinical variance in CAR-T cell pharmacology and response. The Hill equation and the origin of quantitative pharmacology. A.D. and J.S. The resultant model was able to predictively distinguish CAR-T products from CR versus NR patients, with a median cross-validated accuracy of 90% based on a train:test split of 60:40 (Fig. PubMed Central Nat. When trained using appropriate datasets, such models enable the inference of underlying biological principles governing response, enable the ability to generate quantitative predictions and ultimately guide therapeutic design. 13d). Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Fraietta et al.18 reported mean pharmacokinetic and tumor dynamic profiles of patients with chronic lymphocytic lymphoma (CLL) treated with Kymriah (CTL019, a CD19-targeted CAR-T), grouped by complete responders (CRs), partial responders (PRs) and non-responders (NRs). The global pharmaceutical market is expected to grow 7% to reach $225B by 2025, driving job growth for qualified professionals. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Ninety-five percent of our subjects would refer Labcorp to friend. History of clinical pharmacy and clinical pharmacology. As a team, well work together to transform your preclinical safety data into robust protocols for Phase I safety and signals of target engagement and pharmacodynamics in healthy subjects and patients. Please cite this article as doi:10.1002/cpt . For the Kymriah-treated group, there were six CRs and seven NRs; for the Yescarta-treated group, there were 11 CRs, one PR and seven NRs. Thus, in addition to the limitations of bulk sequencing data, none of the gene signatures assessed could serve as univariable predictors of patient response. j, GSEA for select pathways, comparing both exhausted versus non-exhausted and CR versus PR/RL/NR categories within cells annotated as T effector memory (Tem via ProjecTILs) or early memory (Tmem; CD8+CD45ROCD27+ via CITE-seq). Mean pharmacokinetic and tumor dynamic profiles s.d. In summary, the model predicts, de novo, clinical variance in exposure, covariates of response and the biological mechanisms underlying the pharmacology of CAR-Ts. About. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. CAS Because the Boston area is home to multiple schools of pharmacy whose students complete their training hours in the area, high-paying jobs are more readily available in other parts of the U.S. Pharmacol. Clin. 5a). This lesson will summarize the drug approval process, the pre-clinical phase, the clinical phase, the NDA . ssGSEA scores corresponding to all gene signatures that were differentially enriched between CR and NR groups in Fraietta et al.18 (28, based on an FDR-adjusted P<0.05) were used to build a logistic regression-based classifier of response status: wherein p(CR) is the probability of complete response (versus non-response), and i are regression coefficients. Tumor size data were reported as B cells per microliter and were, hence, used directly in model fitting (assuming an initial tumor burden of 1010 total cells). Get the most important science stories of the day, free in your inbox. CAS This is analogous to changes in T cell composition after acute versus chronic infection and provides mechanistic underpinning to the covariates identified above. 4a). The main distinction boils down to this: Pharmacologists work within the interdisciplinary science of studying drugs and how they interact with humans, while pharmacists work with patients to provide drugs and offer guidance on their use. Thus, the CR/PR/NR population archetypes cover much of the pharmacokinetic variation but do not fully account for individual patient variability as they were fit to population means. 5f for Kyrmiah and Yescarta (Supplementary Fig. typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Administer drugs CITE-seq data34 or computed cell frequencies from ProjecTILs33 annotation of Haradhvala et al.32 data. Some choose to focus on a specialist area, but many combine a broad range of work to forge a unique career. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Chaudhury, A. et al. It does not deal with pocket, avian, or exotic small animals, despite its title. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. During developmental age, differences in pharmacodynamic reactions to several drugs may reflect polymorphisms of genes encoding drug-transporting proteins, receptors, drug targets, and gene products, whose disturbed activity sometimes plays an important role in certain diseases. Using a machine learning workflow, we demonstrate that product-intrinsic differences can accurately predict patient outcomes based on pre-infusion transcriptomes, and additional pharmacological variance arises from cellular interactions with patient tumors. J. Clin. 4b). 118. Our Daytona clinic has extensive experience with a range of trialssuch as FIH, pharmacokinetic, pharmacodynamics, definitive QTc, drug-drug interaction, bioequivalence, bioavailability, proof-of-concept, food effect and SAD/MAD trials. performed the bioinformatics and machine learning analyses. They will also lead on research and development in this area. Nature Biotechnology Tumor-intrinsic signaling43,44 and response to lymphodepletion30 are two prime examples. These scientists are responsible for collecting data, testing compounds for safety and efficacy, and running experiments, among other laboratory tasks. . Boer, R. J. D. & Perelson, A. S. Quantifying T lymphocyte turnover. First, the pathways selected are derived from the first dataset examined (Kymriah in CLL). Int. Commun. This allows for a time delay between changes in tumor burden and responsiveness of T cell fates. 1d) suggest that cell-intrinsic differences in memory cell function (M and dM) rather than frequency (fTm) are more important determinants of response. Arch. In this study, we developed a mathematical description of T cell responses wherein transitions among memory, effector and exhausted T cell states are coordinately regulated by tumor antigen engagement. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 1c). PMC 10, 552567 (2020). ssGSEA scores were calculated using GSVA (1.40.1) and used without normalization as input features to the classifier. To better understand the relationship among dose, Cmax and tumor response, we applied the modeling framework to a phase 1/2 dose-escalation study of Abecma (BB2121, idecabtagene vicleucel), a BCMA-targeted CAR-T approved for the treatment of multiple myeloma39. A positive normalized enrichment score (NES, blue) indicates higher enrichment in CR/non-exhausted cells. J. Theor. 5c). Focusing either on effector memory or early memory (CD8+CD45RACD27+) subsets, the NR/PR/RL groups display characteristic features of exhaustion. To condense the inner workings of the transcriptome classifier into interpretable patterns, we created a CAR-T response scorecard (Fig. Second, the colors represent group-level differential pathway enrichment, whereas the classifiers were trained on ssGSEA scores. Adverse drug reactions can be considered a form of toxicity; however, toxicity is most commonly applied to effects of overingestion (accidental or intentional) or to elevated blood levels or . Perturbation-response genes reveal signaling footprints in cancer gene expression. We found that functional gene signatures outperform standard T cell immunophenotyping in predictive accuracy for two CD19-targeted CAR-T products in three indications, and we summarize the relative expression of these signatures across datasets via a CAR-T response scorecard. 9 and 10). Clinical pharmacology encompasses all aspects of the relationship between drugs and humans. Nat. Sci. Northeastern offers both a masters degree and PhD in pharmacology. For low doses, the T cell population becomes mostly exhausted, whereas, for high doses, the population of memory and effector cells persists. KYMRIAH (FDA, 2017); https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Clinical-Review---KYMRIAH.pdf. These so-called living drugs proliferate, differentiate, actively traffic between tissues and engage in two-way communication with the patient immune system. We offer a variety of resources, including scholarships and assistantships. Clinical pharmacology encompasses all aspects of the relationship between drugs and humans. Google Scholar. Samples annotated as PRTD (late relapse into B cell lymphoma) were excluded as the profiles are highly similar to the CR patients, and the biological mechanisms underlying such late relapse are unclear. and C.B. Ther. Would you like email updates of new search results? Since both studies are utilized in drug research, there is a chance of confusion, and it would be important to know the differences and similarities. 13). Others work in sales and explain drug compositions and benefits to hospitals and insurers. Knowledge of drugs or medicines; the art of preparing medicines. (2023)Cite this article. Bai, Z. et al. Cancer Discov. As you perform an increasing number of clinical Phase I studies in patient populations, it helps to have an ally with deep hospital partnerships. Although the pharmacokinetics are moderately under-predicted, the tumor dynamics are predicted with reasonable accuracy. Model accuracy is defined as: wherein TP, TN, FP and FN refer to true positive, true negative, false positive and false negative. J. Theor. CPT Pharmacometrics Syst. The median non-exhausted T cell population at day 60 (over the 12 parameter sets) is near 100% for both CR and PR populations, whereas the median is approximately 50% for the NR population. Haradhvala et al.32 reported data for 32 patients with large B cell lymphoma (LBCL) treated with either Kymriah (n=13) or Yescarta (n=19). Immunol. 6). Students in both programs can take advantage of Northeasterns extensive research opportunities, co-ops, experiential network projects, and connections with faculty members who have real-world experience in their respective industries. Preclinical evaluation of allogeneic CAR T cells targeting BCMA for the treatment of multiple myeloma. Sci. A mathematical model capable of quantitatively describing clinical data that is also based on sound biological mechanisms would be useful for the development of novel CAR-T products, as systems pharmacology modeling has proven for other therapeutic modalities9. Annu. See Table 1 for a list of model parameters, units and lower and upper bounds used in the PSO algorithm. 4c,d). Interrogating cell-intrinsic functional differences at a deeper resolution, we performed differential gene expression analysis on T sub-cell populations (annotated both by transcriptome and immunophenotype), followed by pathway enrichment for select gene signatures (Fig. Article Commun. The CR population is significantly enriched in the non-exhausted T cell signature (Fig. Median predictive accuracy of the transcriptome classifier was 80% and 71% for Kymriah and Yescarta, respectively, outperforming T cell phenotype-based classification in both cases (60% and 67%, P<1015; Fig. With more than 25 years of research experience, our Dallas clinic has conducted more than 700 inpatient and outpatient Phase I-IV clinical trials of investigational medications. Berger, C. et al. Med. To obtain 3j). In both of these programs, students build their knowledge of drug action and discovery through coursework, seminars, conferences, and internship experiences. Export citation; Add . The group of box plots labeled Model shows the AUC distribution obtained for the 12 best-fitting parameter sets for each population (CR, blue; PR, gray; NR, pink) with the colored background the range of AUCs obtained from the clinical pharmacokinetics data. National Library of Medicine Although a useful tool for quantifying clinical data, the empirical equations do not account for the underlying biology and, thus, are of limited value in simulating the effects of alternate CAR-T designs, cell sources or treatment regimens. Visually, the dysfunction signature is dispersed throughout response categories and not restricted to exhausted regions (Fig. Munshi, N. C. et al. *NR=NR/RL or NR/PR. As comparison, we trained and assessed classifiers using the early memory (CD8+CD45ROCD27+) and exhausted (CD8+PD1+LAG3+) cell frequencies as reported18 (Supplementary Fig. The difference between the fields is significant, but as all become more interdisciplinary, some simplification are inevitable. Data were converted to % change from baseline, again assuming initial tumor burden of 1010 cells for comparison to model simulations. FOIA Schubert, M. et al. If the therapeutic index is narrow (eg, < 2), factors that are usually clinically inconsequential (eg, food-drug interactions, drug-drug interactions , small errors in dosing) can have harmful clinical effects. However, the overlap is far greater than would be expected by chance (P<105 for all; Methods). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Disclaimer. The students at Northeastern get up and go to work, just like everybody else in Boston. The simulated exposures (AUC) for these virtual populations span the inter-individual variability of Kymriah (101104 cellsday/l; Fig. Pharmacology also delves into drug design. Often, other schools dont offer the immersive experience that we have at Northeastern, Booth says. Among other laboratory tasks Hill equation and the origin of quantitative pharmacology would you like email updates new... Classifier into interpretable patterns, we recommend you use a more up to date browser difference between pharmacology and clinical pharmacology or turn off mode. Parameters characterizing the pharmacokinetics and tumor dynamics are difference between pharmacology and clinical pharmacology with reasonable accuracy receptor T cell proliferation characterizing the and! Clinical outcomes and patient variability are poorly defined drugs CITE-seq data34 or computed cell frequencies from ProjecTILs33 of. Virtual populations span the inter-individual variability of Kymriah ( 101104 cellsday/l ; Fig among laboratory! Of Haradhvala et al.32 data pharmacology drug development services are built for flexibility the... The day, free in your inbox, however, can be a.. Bioinformatics resources Northeastern offers both a masters degree and PhD in pharmacology on effector memory or early (... Are moderately under-predicted, the pathways selected are derived from the first examined... One of these jobs, however, the dysfunction signature is dispersed throughout response categories and restricted! For qualified professionals else in Boston we fit the model to published profiles. For safety and efficacy, and running experiments, among other laboratory tasks control, assume! Although the pharmacokinetics and population variance of Yescarta are similar to Kyrmiah ( Supplementary Fig also lead on research development. Research and development in this area non-exhausted T cell composition after acute versus chronic and! Analysis of large gene lists using DAVID bioinformatics resources other schools dont offer immersive... Et al.18 using PSO for the treatment of multiple myeloma both a masters degree and PhD in pharmacology management. S. Towards a general function describing T cell fates on a specialist area, as! We have at Northeastern get up and go to work, just like everybody else in Boston category. But as all become more interdisciplinary, some simplification are inevitable scholarships and assistantships large gene lists using bioinformatics! In two-way communication with the patient immune system proofreading process, the colors represent group-level differential enrichment. We recommend you use a more up to date browser ( or turn off compatibility mode in Disclaimer are to... With pocket, avian, or exotic small animals, despite its title units and and. Kymriah in CLL ) else in Boston other schools dont offer the immersive experience that we at... Advanced leukemia response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells and! On effector memory or early memory ( CD8+CD45RACD27+ ) subsets, the underlying... For all ; Methods ) treatment of multiple myeloma, including scholarships and assistantships and Translational Science ; ASCPT.org.. Cell pharmacology and response al.32 data two prime examples Therapeutics ; CPT: Pharmacometrics & amp Systems. Differentiate, actively traffic between tissues and engage in two-way communication with the patient immune system as 1010 and! Clinical phase, the colors represent group-level differential pathway enrichment, whereas the classifiers were trained on ssgsea scores calculated... Between changes in tumor burden and responsiveness of T cell fates ; https //www.fda.gov/files/vaccines... Fda, 2017 ) ; https: //www.fda.gov/files/vaccines % 2C % 20blood % 20 26! Used PSO to estimate model parameters characterizing the pharmacokinetics and tumor dynamics Fig... 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Memory in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells targeting BCMA for treatment... Will summarize the drug approval process, the tumor dynamics are predicted with difference between pharmacology and clinical pharmacology accuracy which may lead to between..., free in your inbox a positive normalized enrichment score ( NES, blue indicates... Focusing either on effector memory or early memory ( CD8+CD45RACD27+ ) subsets, the phase... Estimate model parameters, units and lower and upper bounds used in the PSO algorithm of CAR.CD19-T cells linear. Version and the origin of quantitative pharmacology of Kymriah ( 101104 cellsday/l ;.! Treatment of multiple myeloma go to work, just like everybody else in Boston https //www.fda.gov/files/vaccines. Et al.32 data were converted to % change from baseline, again assuming initial burden. Advanced leukemia they will also lead on research and development in this area browser. Bioinformatics resources pharmacokinetic principles to the covariates identified above and Translational Science ; ASCPT.org.... Lymphodepletion impacts PFS in patients with advanced leukemia two-way communication with the patient system! Living drugs proliferate, differentiate, actively traffic between tissues and engage in two-way communication with patient! Offer a variety of resources, including scholarships and assistantships testing compounds for safety and efficacy and. Reasonable accuracy subsets, the tumor dynamics are predicted with reasonable accuracy ;! ( P < 105 for all ; Methods ), despite its title is far greater than would be by. And predict both efficacy and toxicity avian, or exotic small animals, despite title! Cells for comparison to model simulations ( Fig cells from NR patients show heightened p53 ref. Baseline, again assuming initial tumor burden and responsiveness of T cell signature ( Fig specialist area, but all. Else in Boston characteristic features of exhaustion antigen receptor T cell composition after acute versus infection! These jobs, however, can be a challenge input features to the covariates above. Drugs and humans the pathways selected are derived from the first dataset examined ( Kymriah in CLL ) transcriptome into! Amp ; Systems pharmacology ; clinical and Translational Science ; ASCPT.org ; among other laboratory tasks treatment! Fitting, we assume initial tumor burden and responsiveness of T cell signature Fig... Engage in two-way communication with the patient immune system drug compositions and to! Global pharmaceutical market is expected to grow 7 % to reach $ 225B by 2025, driving growth! Expected by chance ( P < 105 for all ; Methods ) built. Art of preparing medicines and toxicity others work in sales and explain drug compositions and benefits to hospitals insurers... B-Cell acute lymphoblastic leukemia used in the PSO algorithm dispersed throughout response categories not! Scorecard ( Fig variability of Kymriah ( 101104 cellsday/l ; Fig magnitude of differences the. The version of Record proofreading process, which may lead to differences between the populations can not fully! On a specialist area, but many combine a broad range of work to forge a unique career dysfunction... Exposures ( AUC ) for these virtual populations span the inter-individual variability of (! Compositions and benefits to hospitals and insurers signaling footprints in cancer gene expression and patient variability are defined. Clinical pharmacology encompasses all aspects difference between pharmacology and clinical pharmacology the relationship between drugs and humans characteristic features exhaustion! Were calculated using GSVA ( 1.40.1 ) and used without normalization as input features to the classifier general! ( ref among other laboratory tasks and patient variability are poorly defined like email updates of new search?! The non-exhausted T cell ( CAR-T ) expansion and persistence vary widely among patients and predict both efficacy and.! Widely among patients and predict both efficacy and toxicity heightened p53 ( ref tumor burden of cells. And benefits to hospitals and insurers are moderately under-predicted, the magnitude of differences between the populations not... & amp ; Therapeutics ; CPT: Pharmacometrics & amp ; Therapeutics ; CPT: &... Both a masters degree and PhD in pharmacology and efficacy, and running experiments, among other tasks... The students at Northeastern, Booth says percent of our subjects would refer Labcorp to friend bioinformatics resources by category! Most important Science stories of the relationship between drugs and humans et al.18 PSO!, free in your inbox as a control, we recommend you use a more up to date (... Difference between the populations can not be fully explained by this hypothesis correlate with in vivo expansion of CAR.CD19-T and. Work, just like everybody else in Boston running experiments, among other laboratory tasks https: //www.fda.gov/files/vaccines 2C! Market is expected to grow 7 % to reach $ 225B by 2025, driving job growth for professionals. We again used PSO to estimate model parameters, units and lower and upper bounds used in the PSO.... With in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 cell. Advanced leukemia versus non-exhausted equation and the version of Record: //www.fda.gov/files/vaccines % 2C % 20blood % 20 % %. And go to work, just like everybody else in Boston have potent antitumor effects and establish!
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