car t cell therapy vs monoclonal antibodies

In the lab, Dumbrava says, the T cells are modified to produce the CAR, which allows the T cells to attach to specific antigens on the tumor cells. All the components of mouse mAbs are derived from mice. This article sets out that case, but personally, I see room in the clinic for both. This drug is infused into a vein (IV), usually 3 times a week for up to 12 weeks. In contrast to CAR T cells, blinatumomab has an in vivo half-life of 2 to 4 hours and requires continuous IV infusion. David H. Vesole, MD, PhD, discusses the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice. CAR T-cell Therapy: A New Era in Cancer Immunotherapy DeVita, Hellman, and Rosenbergs Cancer: Principles and Practice of Oncology. However, the dose of CAR T cells used in these trials varies and also differs among recipients within a single trial. When we combine belantamab mafodotin with other active agents with different mechanisms of action, we can see superior response rates and remission durations. Pembrolizumab can be used to treat primary mediastinal large B-cell lymphoma (PMBCL) that has not responded to or has come back after other therapies. For patients who have multiple myeloma and adequate physiologic organ function, and agree to [undergo] transplant, transplant is considered standard. Anti-cancer pro-inflammatory effects of an IgE antibody targeting the Version 5.2018. Neelapu SS, Locke FL, Bartlett NL, et al. They are tolerated better and their efficacy is better than conventional chemotherapy. It is exciting to know that we have these monoclonal antibodies, which target specific surface components of myeloma cells. T cells are removed from a patient through a process like a blood draw. Other side effects can depend on which drug is given. The relevance of blinatumomab prior to treatment with CD19 CAR T cells is still under investigation with conflicting reports emerging. OncLive: What makes BCMA a logical target in multiple myeloma? Please enable it to take advantage of the complete set of features! Tumor flare: This drug might cause your tumor to grow or cause more symptoms for a time, which is known as tumor flare. CRS occurs in almost all patients treated with CAR T-cell therapy; in fact, the presence of CRS is a diagnostic marker that indicates the CAR T-cells are working as intended to kill . Weve invested more than $5 billion in cancer research since 1946, all to find more and better treatments, uncover factors that may cause cancer, and improve cancer patients quality of life. Thalidomide can also cause drowsiness, fatigue, and severe constipation. The most common side effects are fever, chills, nausea, and rashes. Many trials have looked at triplets versus doublets, and essentially all of them show that triplets are superior to doublets in the frontline and relapsed/refractory settings. Therefore, since 2003, [multiple drugs have been] approved for the treatment of myeloma. Dual-specific antibody constructs and CAR T cells are being developed to counteract monotargeting escape. Brentuximab vedotin (BV) is a conjugate containing an anti-CD30 monoclonal antibody and a microtubule-disrupting agent, monomethyl auristatin E (MMAE). 2019;16:235245. Belantamab mafodotin-blmf (Blenrep) received regulatory approval in August 2020. Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in Bispecific T cell engagers: an emerging therapy for management of Serious side effects from this release can include: High fever and chills. Marion Subklewe; BiTEs better than CAR T cells. It is approved for use in patients with follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. In the r/r setting, antigen loss and other adaptive immune escape strategies counteract the initial higher response rate of CD19 CAR T cells. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Low blood cell counts: This drug might lower your blood cell counts, which can increase your risk of infections or bleeding. It is an ADC where the antibody is directed against BCMA and is conjugated to a chemotherapy drug. . This drug can be used along with lenalidomide (see Immunomodulating drugs, below) to treat diffuse large B-cell lymphoma (DLBCL) that has come back or is no longer responding to other treatments, in people who cant have a stem cell transplant for some reason. CAR T-cell therapy can cause toxicities, but in contrast to lymphoma and leukemia, most of them are minor in multiple myeloma. Emerging data indicate that [quadruplets] are even more efficacious without a significant increase in toxicity. -, Veisi Malekshahi Z, Hashemi Goradel N, Shakouri Khomartash M, Maleksabet A, Kadkhodazadeh M, Kardar GA, et al. It is approved for the treatment of r/r BCP-ALL, as well as BCP-ALL with minimal residual disease (MRD).4,5, Several aspects favor the application of bispecific T-cellrecruiting antibody constructs compared with the application of CAR T cells (Table 1). Monoclonal antibodies and cancer treatment: What to know Although quadruplets are quite effective up front, they are not FDA approved at this point in time. More serious reactions can include chest pain, heart racing, swelling of the face and tongue, cough, trouble breathing, feeling dizzy or lightheaded, and feeling faint. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. These include: These drugs are given into a vein (IV), often over several hours. The .gov means its official. Finally, both treatment platforms are associated with high financial toxicity. 2) in that they can: 1) redirect specific polyclonal immune cells such as T cells and NK cells to tumor cells to enhance tumor killing, 2) simultaneously block two different pathways with unique or overlapping functions in pathogenesis, 3) potentially increase binding specificity by Philadelphia, Pa: Elsevier; 2014. CAR-T- and a side order of IgG, to go?- Immunoglobulin . The great advantage of this approach is an increase in the safety profile, as the infusion can be stopped at any time, thereby reversing immune activation and immune-related adverse events. How do you see CAR T-cell therapy impacting the landscape of multiple myeloma? 5th ed. This happens most often within the first day after the infusion, and it can be serious or even life-threatening. Tisa-cel achieved a 52% ORR, including a 40% CR rate, in adult patients with r/r DLBCL in the JULIET trial. DREAMM-2 is the phase 2 trial that led to the FDA approval for the drug. In addition, antigen-targeted approaches of monoclonal antibodies, CAR-T cell therapy, and TCR-based therapy have shown varied successes against . DREAMM-3 through DREAMM-16 [are trials] that are evaluating a variety of other agents to be added to belantamab mafodotin. CAR T-cell therapy is likely going to be approved sometime in the first quarter of 2021. [Historically], we would see, at most, a 20% likelihood of achieving a complete remission (CR). Biologically, the monoclonal antibody attaches to the myeloma cell, which is endocytosed into the cell. Before each dose of [belantamab mafodotin], which is administered every 3 weeks, patients have to be seen by an ophthalmologist or optometrist to be cleared before receiving the next dose of therapy. In the vast majority of patients, this is very minor and presents as blurred vision or dry, scratchy eyes. BCMA stands for B-cell maturation agent, and all myeloma cells have some expression of BCMA on their cell surface. I imagine that in the future, patients are going to get 4 or 5 different drugs, some specific to enzyme pathways, others specific to their individual DNA sequencing. Overall survival (OS) [rates] have improved as well [compared with] when I first started more than 30 years ago. Are CAR T cells better than antibody or HCT therapy in B-ALL? Physician Data Query (PDQ). -, Martin FL, Martinez EZ, Stopper H, Garcia SB, Uyemura SA, Kannen V. Increased exposure to pesticides and colon cancer: Early evidence in Brazil. Clearly, challenges in production, manufacturing, and safety should be balanced against response rates. They all can cause reactions during the infusion (while the drug is being given) or several hours afterward. Together, were making a difference and you can, too. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and . of treatment applications: 1; additional costs: logistics, leukapheresis, lymphodepleting chemotherapy, average 10-d in-hospital stay (outpatient to long-term stay, including ICU), possible IgG-replacement therapy for months to years, High flexibility to combine different BiTE constructs given in parallel or sequentially, dual-specific BiTE constructs in clinical trials, individualized combinatorial approach of targeting BiTE construct and immunomodulatory construct feasible, Various dual-targeting CAR T-cell constructs in clinical trials; possibility to apply simultaneously vs sequentially, Potentially, reversal through treatment-free intervals (induction: 4 wk on, 2 wk off; maintenance: 4 wk on, 8 wk off), Preclinical work: drug-induced cessation of CAR receptor signaling to prevent or reverse exhaustion; genetically engineered CAR T cells to counteract exhaustion. CD5 CAR-T-cell therapy obtained an ORR of 44.4% (4/9), with a patient with AITL achieving CR . It can also cause some other, more serious side effects, including: Cytokine release syndrome (CRS): This side effect can occur when T cells in the body release chemicals (cytokines) that ramp up the immune system. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf on May 2, 2018. There is a grading system from 1 to 4 with regard to how involved the ophthalmologic abnormalities are. Abstract #577. Lancet Oncol. Bispecifics vs CAR T-Cell Therapy: Which Is Better in Relapsed The use of adapter CAR T cells is aimed at combining the benefits of BiTE molecules with the power of ex vivoactivated CAR T cells. Could you describe the unique safety profile of belantamab mafodotin? The structure of different types of mAbs. Other novel formats, such as the multifunctional antibody construct that targets a tumor-associated antigen with high affinity and blocks an inhibitory checkpoint molecule with low affinity, will be tested.29 Alternative constructs elicit a combination of simultaneous blockade of immune checkpoint molecules and costimulation30 or provide targeting and stimulating within one construct.31 Also, the CAR T-cell platform enables different strategies to be used to block the inhibitory PD-1 signal, including CRISPR-Cas9mediated PD-1 disruption. Clipboard, Search History, and several other advanced features are temporarily unavailable. Loncastuximab tesirine (Zynlonta):This antibody-drug conjugateis used by itself to treat some types of large B-cell lymphoma (including diffuse large B-cell lymphoma, or DLBCL) after at least 2 other treatments (not including surgery or radiation) have been tried. The investigators are giving individual drugs, based on the patients DNA sequencing, that will attack specific abnormalities. However, looking at grade 3 CRS and ICANS in blinatumomab-treated patients, the event rate was much lower compared with the CAR T trials, with 4.9% for CRS and 9% for ICANS. This drug can cause some of the same side effects as other antibodies that target CD20, including infusion reactions (see above). CAR T-Cell and Monoclonal Antibodies - Spherical Hysterical Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Chimeric antigen receptor (CAR) T-cell therapy: This therapy takes some T-cells from a patient's blood, . Park et al22 reported on long-term follow-up of CD19-CD28 CAR T cells in a pediatric BCP-ALL population (n = 53). Immunotherapy vs Chemotherapy: Uses, Similarities & Differences Given this risk, the company that makes these drugs puts restrictions on access to them to prevent women who are or might become pregnant from being exposed to them. Monoclonal Antibodies - NCI - National Cancer Institute Belantamab mafodotin was approved in kind of a niche sense in that it is approved for patients who had 4 prior lines of therapy. In the ZUMA-1 trial, axi-cel treatment achieved an overall response rate (ORR) of 82%, including a 54% complete response (CR) with 1 year of follow-up, and 52% overall survival rate at 18 months in refractory large B-cell lymphoma. Whether you or someone you love has cancer, knowing what to expect can help you cope. This brings the two together, which helps the immune system attack the lymphoma cells. On the other hand, graft-versus-host disease and rejection of CAR T cells might counteract the benefit of allogeneic cell products.12, Comparison of blinatumomab vs CD19 CAR T cells. The approach allows targeting of several antigens simultaneously to decrease toxicity through an on-off adapter molecule with a short half-life and counteract T-cell exhaustion with treatment-free intervals. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Curr Opin Pharmacol. Seven cases had product-related issues.7 However, in the pivotal ZUMA-1 trial, the manufacture of axi-cel failed for only 1 of 111 patients. Version 3.2018. At the American Cancer Society, we have a vision to end cancer as we know it, for everyone. 2018;8(2): 131-132; DOI: 10.1158/2159-8290.CD-NB2017-179. Although the first phase 1 trial with blinatumomab was conducted in patients with B-cell neoplasia,16 further developments in r/r DLBCL were compromised by the need for higher dosing, which led to an increase in ICANS. The DREAMM-1 study essentially [evaluated whether] belantamab mafodotin had any activity [in patients with relapsed/refractory multiple myeloma]. Because of these kinds of reactions, drugs to help preventthem aregiven before each infusion. Tell your health care team if you notice tender or swollen lymph nodes, chest pain, cough, trouble breathing, or pain or swelling around a known tumor. Interestingly, a common denominator of response was identified across trials: patients treated in the setting of MRD had a significantly better response and long-term survival compared with patients with a high tumor load.5,20 A comparison of clinical trials revealed that the recurrence-free survival in patients (n = 255) treated with blinatumomab in the MRD setting (MRD cutoff: 103) was 35.2 months vs 7.3 months in the r/r setting (n = 271).4,21 For CAR T cells, the number of reported patients treated in the MRD setting is much lower, and no MRD-focused trials have yet been reported. We can also help you find other free or low-cost resources available. The authors declare that they have no competing interests. The FDA approval of belantamab mafodotin was based on data from the DREAMM-2 trial. Schuster S., et al. Allogeneic CAR T-cell therapy opens [the option] up for those patients, as well as for the patients who need treatment sooner rather than later; some patients cannot wait 2 to 4 weeks for the cells to be generated. Bookshelf Accessed at https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq on May 3, 2018. Our team is made up of doctors andoncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing. This article has a companion Point by Molina and Shah. Rituxan was the original brand name for rituximab, but several similar versions (calledbiosimilars) are now available as well, including Ruxience, Truxima, and Riabni. Currently, triplet therapy seems to be the standard of care, but what is evolving is whether we should give quadruplet regimens with monoclonal antibodies in addition to those same 3 classes of drugs I mentioned. Therefore, we generally use triplet regimens for initial therapy. The antibody finds the lymphoma cell and attaches to the surface protein CD79b. Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors [These triplets] are based on different categories of drugs such as PIs, immunomodulatory drugs (IMiDs), and corticosteroids. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Right now, belantamab mafodotin is being given as a single agent. It can take 5-7 minutes to inject the drug, but this is much shorter than the time it normally takes to give the drug by vein. To me, this is the most exciting area because it is a one-and-done [approach] versus continued therapy. Selinexor is an [oral] pill given once or twice a week, depending on the schedule. [Moreover,] there is at most a 10-day window in which these abnormalities occur, after which patients are essentially home free for the duration of time the cells are effective. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. -, Thanikachalam K, Khan G. Colorectal cancer and nutrition. Bispecific proteins (recombinant proteins that simultaneously bind 2 different antigens) and chimeric antigen receptors (CARs) facilitate T-cellmediated killing of malignant cells by redirecting autologous T lymphocytes to cell-surface antigens on cancer cells. The agent was only tested in patients who had 4 or more lines of therapy. CAR T cells are patients own lymphocytes that are genetically modified to improve their activity in targeting their own myeloma cells. Below are some of the resources we provide. CEA plasmid as therapeutic DNA vaccination against colorectal cancer. AE, adverse event; ICU, intensive care unit; IgG, immunoglobulin G; Ph, Philadelphia chromosome; PMBCL, primary mediastinal B-cell lymphoma; SOC, standard of care; Tx, treatment; WBCs, white blood cells. Methods: Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient's autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. T-cell transfer therapy. In chimeric mAbs, the variable regions of a mice Ab is fused with the constant regions of a human Ab. This site needs JavaScript to work properly. Adult Non-Hodgkin Lymphoma Treatment. Although they are not currently the standard of care, I anticipate within the next 5 years that they will become the standard of care potentially up front, as well as in the relapsed/refractory settings for patients with multiple myeloma. These treatments can also sometimes cause serious, Other serious side effects of these treatments can include. HHS Vulnerability Disclosure, Help Nervous system problems: This drug might affect the nervous system, which could lead to symptoms such as headaches, numbness or tingling in the hands or feet, feeling dizzy or confused, trouble speaking or understanding things, abnormal sleep patterns, tremors, or seizures. This type of treatment enhances the ability of your T cells to recognize and attack cancer cells. It can also cause very low white blood cell counts, which increases the risk for serious infections. This is done by replacing part of the antibody polypeptide with a fragment of a microbial antigen. The https:// ensures that you are connecting to the Lisocabtagene maraleucel (Breyanzi, also known as liso-cel) is approved to treat adults with diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and follicular lymphoma grade 3B, after at least one other kind of treatment has been tried. Selinexor (Xpovio) is another drug that was recently approved for patients who have had 4 prior lines of therapy. Amandeep Godara, MBBS, of @huntsmancancer, discusses important patient factors to consider when deciding between a CAR T-cell therapy vs bispecific antibody in relapsed/refractory multiple myeloma. With CAR T cells, patients get their therapy, get their response, and may not require treatment for an extended period of time. As well as personalized individual treatments using BiTEs or CAR T cells, one innovative way this could manifest itself is in the combination of BiTEs as an adapter strategy with universal CAR T cells that might overcome the clinical stings of T-cell dysfunction while maintaining the benefits of BiTE constructs. Over recent years, bispecific antibodies have been engineered in >50 different formats, including dual-affinity retargeting proteins, tandem diabodies, and bi-nanobodies, but in oncology, the bispecific T-cell engagers (BiTEs) are the most developed and thus are the focus of this article.1 Both BiTE and CAR approaches are independent of the specificity of the endogenous T-cell receptor and independent of major histocompatibility complex on tumor cells. N Engl J Med. Mosunetuzumab can be used to treat follicular lymphoma that has returned or that is no longer responding after treatment with at least 2 other types of drugs. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Dexamethasone was used in the TOWER trial prophylactically to prevent CRS and neurologic events; thus, blinatumomabs safety in this regard cannot be compared with tisa-cel or axi-cel. We are going to have a whole list of additional options with these BCMA-directed therapies in the very near future. Federal government websites often end in .gov or .mil. We couldnt do what we do without our volunteers and donors. Other side effects can include feeling tired, rash, fever, and headache. Whether you want to learn about treatment options, get advice on coping with side effects, or have questions about health insurance, were here to help. These receptors can attach to proteins on the surface of lymphoma cells. The first-generation CAR-T cells only contain one intracellular, MeSH Age was a particularly variant factor between study cohorts. Version 3.2018. Toxicity and management in CAR T-cell therapy, Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management, How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies, Tumor regression in cancer patients by very low doses of a T cell-engaging antibody, Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma, Open-label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma [abstract], Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor therapies and is active in treatment through multiple lines [abstract], Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL, Blinatumomab vs historic standard-of-care treatment for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukaemia, Long-term follow-up of CD19 CAR therapy in ALL, Tumor antigen escape from CAR T cell therapy, Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies, Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia, Mechanisms of resistance to CAR T cell therapy, Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL, PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR, Bifunctional PD-1 CD3 CD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia, Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy, BCMA-targeting bispecific antibody that simultaneously stimulates NKG2D-enhanced efficacy against multiple myeloma, Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL, Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment, Pharmacologic control of CAR-T cell function using dasatinib, Emerging approaches for regulation and control of CAR T cells: a mini review, Value and affordability of CAR T-cell therapy in the United States, Clinical lessons learned from the first leg of the CAR T cell journey, The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells, Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell, Long-term follow-up of serum immunoglobulin levels in blinatumomab-treated patients with MRD-positive BCP-ALL, Outcome of patients with relapsed/refractory ALL after blinatumomab failure: No change in the level of CD19 expression, T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts, c-Jun overexpression in CAR T cells induces exhaustion resistance, 2021 by The American Society of Hematology, Copyright 2023 by American Society of Hematology, BiTE vs CAR T-cell availability: off the shelf vs individualized good manufacturing practices production, https://doi.org/10.1182/bloodadvances.2020001792, Blinatumomab: pediatric and adult patients with r/r ALL, MRD, Axi-cel: adult with r/r (>2 prior Tx lines) DLBCL, PMBCL, Tisa-cel: r/r ALL <26 y of age, adults with r/r (>2 prior Tx lines) DLBCL, Blinatumomab: pediatric (>1 y of age) r/r ALL and adults with r/r Ph, Axi-cel: adults with r/r (>2 prior Tx lines) DLBCL, PMBCL, Tisa-cel: r/r ALL <26 y of age; adults with r/r (>2 prior Tx lines) DLBCL, Retro- or lentiviral-transduced CAR T cells, 17-54 d from patient presentation to CAR T transfusion (national vs international patient recruitment, different trial design), CAR T-cell product variability due to differences in T-cell subset composition, CAR transduction efficacy, number of viable CAR T cells; number of transfused CAR T cells differs from 0.2 10, Engineered, commonly using autologous CD4 and CD8 T cells, Relies on endogenous T-cell composition and function at time of infusion, Relies on T-cell composition and function at time of leukapheresis; further modulation of CAR T function after transfusion through patient- and disease-related parameters (eg TME), Lymphodepletion prior to start of therapy, Lymphodepletion with cyclophosphamide and fludarabine prior to CAR T-cell transfusion mandatory (tisa-cel: exceptions in case of WBCs <110, CRS:4.9%, ICANS: 9%, hematotoxicity: neutropenia: 28%; lymphopenia: 1.5%; decrease in white-cell count: 5.2%; decrease in platelet count: 6.4% (lower rate of infections compared with SOC; short half-life (<2 h), interruption possible, CRS: 46%; ICANS: 12%-32%; hematotoxicity: 23%-45%; JULIET trial: cytopenia not resolved by day 28: 32%, CAR T cells persist for months/years, Neoplasia through genetic interference, genotoxic side effects, Recovery after completion of infusion: 6-18 mo, Months to years depending on persistence of functional CAR T cells; hypogammaglobulinemia for months to years, Product: US$72000; average no.

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