most department stores CAR T-Cell Therapy: A Healthcare Professional's Guide - Cancer Targets Medically reviewed on Oct 23, 2017 by L. Anderson, PharmD . Previous 1 of 8 Next View as slideshow Gene Therapy to the Rescue Chimeric antigen receptor (CAR) T-cell therapies are now FDA approval. These agents -- by all means an bioengineering marvel -- are constructed from the patient's own T lymphocytes and then re-infused back into the patient. The re-engineered T cells are then directed to seek out and kill the cancer cells. On August 30, 2017 the FDA approved Kymriah (tisagenlecleucel), from Novartis, for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). In addition, on October 18, 2017 Kite Pharma/Gilead's Yescarta (axicabtagene ciloleucel) was approved to treat adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Naturally occurring T cells aren't always as efficient as they should be in targeting malignancies. Cancers can evade the T-cells, the T-cells become less effective, the T-cells don't replicate appropriately, and they can miss identifying the tumor target as a foreign body. CAR-T can help to re-invigorate the T cell to do its job. Learn More: Structure and Mechanism of Action of CAR T-Cell Therapy The rates of complete response with CAR T in certain leukemias and lymphomas have been impressive, and some patients have been in sustained or partial remissions for years. But it's important to note that many studies are still ongoing for other cancer types. CAR T-Cell Therapy: Cancer Success The primary successes seen with CAR T are with refractory hematologic malignancies such as non-Hodgkin lymphomas (NHL) and B-cell leukemias. The C19 tumor target has been the most common tumor target for these cancers. Yescarta (axicabtagene ciloleucel) was approved for 3 subtypes of aggressive B-cell Non-Hodgkin lymphoma : diffuse large b-cell lymphoma (DLBCL) primary mediastinal large b-cell lymphoma high grade B-cell lymphoma DLBCL arising from follicular lymphoma Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. Other research with axicabtagene ciloleucel includes: Acute Lymphoblastic Leukemia (ALL) Mantle Cell Lymphoma Other cancer types under early phase investigation include: Multiple Myeloma Chronic Lymphocytic Leukemia Acute Myeloid Leukemia Learn More, Including Side Effects of CAR T: CAR T-Cell Therapy: A Healthcare Professional's Guide: KTE-C19 Studies Aggressive B Cell Non-Hodgkin Lymphomas About 90% of lymphoma cases start in the B cells. The C19 tumor target that is sought by the CAR T cell therapy is found on the tumor surface or on B lymphocytes. Other cells are not targeted by the CAR therapy if they do not exhibit the C19 target. Three subtypes of aggressive non-Hodgkin lymphoma approved for Yescarta (axicabtagene) ciloleucel include: Diffuse large B-cell lymphoma (DLBCL) - this is the most common NHL subtype, making up about 30 percent of US cases. DLBCL is aggressive with large masses of B lymphocytes and involves the liver, spleen, bone marrow or other organs. Typically, the treatment for refractory DLBCL is 3rd or 4th line chemotherapy drugs. These patients have a poor prognosis and few treatment options. Transformed follicular lymphoma - Follicular lymphoma is the second most common form of lymphoma in the US, and initially may be slow-growing (indolent). However, the risk for transformation to aggressive lymphoma (usually DLBCL) is roughly 30%. A genetic defect, a specific chromosomal abnormality can result in this type of aggressive lymphoma being resistant to standard treatments. Patients with transformed lymphoma who fail standard chemotherapy have a very poor prognosis. Mediastinal B-cell lymphoma - This is an aggressive form of DLBCL where a large mass forms in the center of the chest and can compress veins need to carry blood and oxygen to the heart. Roughly 2 to 3% of patients with NHL will have this subtype, usually women in their 30's or 40's. Chemotherapy is typically used for treatment; but radiation may also be used. Pivotal Trial: Aggressive B-Cell Non-Hodgkin Lymphoma [Axicabtagene ciloleucel] ( Yescarta ) was the first CAR T-cell therapy approved for non-Hodgkin's lymphoma in the U.S. The multicenter trial submitted to the FDA by Kite Pharma recruited patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who were also ineligible for autologous stem cell transplant. In this pivotal trial known as ZUMA-1 , researchers assessed treatment of aggressive refractory B-cell lymphoma with axicabtagene ciloleucel in 101 patients with three subsets of refractory NHL. Here are the major results: Objective response rate (ORR) of 82%, the primary endpoint, was met ORR at 6 months was 41%, with 36% of patients still in complete response (CR) At 8.7 months, the median overall survival was not yet reached, but a meta-analysis of a similar population receiving recommended approved treatments for refractory NHL ( SCHOLAR-1 study ) had a median OS of 6.6 months. Relapsed/Refractory Acute Lymphoblastic Leukemia Kite Pharma's CAR T-cell therapy is also under research for the treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL) in pediatric and adults patients. Axicabtagene ciloleucel (KTE-C19) is in late-stage Phase 1 studies of r/r ALL with Phase 2 studies starting in 2017. ALL is a cancer of the blood and bone marrow that results in proliferation of immature lymphocytes that are ineffective in fighting infections. In addition, healthy red blood cells from the bone marrow cannot be formed, leading to anemia. There are several approaches to treatment of ALL : Blood transfusions Chemotherapy, targeted cancer therapy Radiation treatment Stem cell transplant Despite these effective treatments, some patients will still relapse over time or be refractory to standard therapy. Investigational CAR T cell therapy has shown impressive results in these difficult-to-treat patients. In the Phase 1 ZUMA-3 and ZUMA-4 trials from Kite Pharma, preliminary analysis found 9 of 11 patients, or 82%, acheived a complete remission or a complete remission with incomplete or partial blood count recovery. In addition, all patients tested negative for minimal residual disease (MRD), which correlates with ALL disease relapse. Relapsed/Refractory Mantle Cell Lymphoma Relapsed or refractory mantle cell lymphoma (r/r MCL) is an uncommon, aggressive and often incurable B cell cancer that makes up roughly 6% of non-Hodgkin lymphomas. Treatment initially involves several standard regimens including rituximab (Rituxan). The targeted drug regimen ibrutinib ( Imbruvica ), a Bruton tyrosine kinase (BTK) inhibitor, was approved in 2013 for patients with relapsed MCL. Autologous stem cell transplantation may also be an option. CAR T is under research in r/r MCL. Studies at the National Cancer Institute (NCI) have demonstrated durable remissions using CAR T-cell therapy in r/r MCL. In the Phase 2 ongoing single arm, open-label, multicenter ZUMA-2 study from Kite Pharma , investigators will enroll 70 patients with r/r MCL whose disease is refractory to or has relapsed following anthracycline- or bendamustine-containing chemotherapy and anti-CD20 monoclonal antibody therapy and ibrutinib. The primary objective of this study is to assess safety and efficacy of axicabtagene ciloleucel by evaluating overall response rate (ORR) defined as partial remission plus complete remission. Secondary endpoints such as duration of response, progression-free survival, and overall survival are also being evaluated. Other ZUMA Studies CAR T-cell therapy has been found to be effective across a wide range of B-cell malignancies. Other ZUMA studies utilizing the engineered axicabtagene ciloleucel regimen include: ZUMA-5: Indolent (slow-growing) NHL, with first patient enrollment expected in the first quarter of 2017 ZUMA-7: 2nd line DLBCL, with first patient enrollment expected in 2017 ZUMA-8: Chronic lymphocytic leukemia (CLL), with first patient enrollment expected in 2017 Learn more: CAR T-Cell Therapy: A Healthcare Professional's Guide - Introduction: The Tumor Solid Tumor Research: Progress to Be Made While CAR T-cell therapy in hematologic cancers is impressive, the fact remains that most deadly cancers are solid tumors like lung, breast, or colon cancer. Efforts are ongoing to understand how CAR T-cell therapy can be utilized to treat solid tumors. New tumor targets will need to be identified. The mechanism of CAR T interactions with a solid tumor as compared to a hematologic malignancy is a priority. To date, most studies of solid tumors being treated with CAR T have failed to respond to treatment and toxicities have been serious. Solid tumors present an inhospitable microenviroment for T cells and lead to anergy (lack of an immune response) of the T cell. However, researchers push on. As reported by Yong, et al in January 2017, over 51 CAR T trials were ongoing (primarily in Phase 1) or planned for solid tumors. CAR T studies listed for solid tumors include: Neuroblastoma, metastatic melanoma and osteosarcoma directed against tumor antigen GD2 Lung, colorectal, ovary, pancreatic directed against tumor antigen EGFR Breast, ovarian, lung, pancreatic, advanced sarcoma directed against tumor antigen HER2 Hepatocellular cancer, squamous cell carcinoma of the lung directed against tumor antigen GPC3 Positive results have been reported for neuroblastoma (GD2) and for sarcoma (HER2). In addition, T cell receptor (TCR) treatment is also under investigation. These engineered autologous T cells may have higher success rates in solid tumors. To research additional enrolling clinical trials for CAR T cell therapy, visit ClinicalTrials.gov . Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - Cancer Targets NEXT UP CAR T-Cell Therapy: A Healthcare Professional's Guide - Yescarta (KTE-C19) Studies Chimeric antigen receptor (CAR) T-cell therapy clinical trial results are impressive in aggressive blood cancers where patients have run out of options. Review the latest clinical data for axicabtagene ciloleucel DON'T MISS Seasonal Allergies: Top Prevention Tips Here, review how to safely pick the allergy medicine that may be right for you. View all slides as one page Print this page Sources Ahmed N, Brawley V, Hegde M, et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;1688 96. Louis C, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011:118; 6050 56. Smith AD. Pivotal Year Looms for CAR T-Cell Therapies. OncLive. March 1, 2017. Accessed October 23, 2017 at http://www.onclive.com/publications/oncology-live/2017/vol-18-no-4/pivotal-year-looms-for-car-tcell-therapies Yong, C, Dardalhon V, Devaud C, et al. CAR T-cell therapy of solid tumors. Immunology and Cell Biology. 2017: 356 63. Accessed October 23, 2017 at https://www.nature.com/icb/journal/v95/n4/full/icb2016128a.html Alamasbak H, Aarvak T, Vemuri M, et al. CAR T Cell Therapy: A Game Changer in Cancer Treatment. J of Immunology Research. 2016: Article ID: 5474602 Newick K, Moon E, Albelda S. Chimeric antigen receptor T-cell therapy for solid tumors. Molecular Therapy Oncolytics. Volume 3, 2016, Article 16006. Accessed October 23, 2017 at http://www.sciencedirect.com/science/article/pii/S2372770516300456 Bernaski R. Looking Ahead: What's New In CAR T-Cell Therapy for Hematologic Malignancies. Cure. March 24, 2017. Accessed October 23, 2017 at http://www.curetoday.com/articles/looking-ahead-whats-new-in-cart-cell-therapy-for-hematologic-malignancies#sthash.wc2O8TXw.dpuf Neelapu S. An Interim Analysis of the ZUMA-1 Study of KTE-C19 in Refractory, Aggressive Non-Hodgkin Lymphoma. Clinical Advances in Hematology & Oncology. Vol. Volume 15, Issue 2, February 2017. Accessed October 23, 2017 at http://www.hematologyandoncology.net/archives/february-2017/an-interim-analysis-of-the-zuma-1-study-of-kte-c19-in-refractory-aggressive-non-hodgkin-lymphoma/ ClinicalTrials.gov. A multi-center study evaluating KTE-C19 in pediatric and adolescent subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (ZUMA-4). https://clinicaltrials.gov/ct2/show/NCT02625480 . Identifier: NCT02625480. Accessed October 23, 2017. ClinicalTrials.gov. A phase 2 multicenter study evaluating subjects with relapsed/refractory mantle cell lymphoma (ZUMA-2). https://clinicaltrials.gov/ct2/show/NCT02601313 . Identifier: NCT02601313. Accessed October 23, 2017. ClinicalTrials.gov. A study evaluating KTE-C19 in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) (ZUMA-3). https://clinicaltrials.gov/ct2/show/NCT02614066 . Identifier: NCT02614066. Accessed October 23, 2017. KTE-C19 Approval Status. FDA Status. Drugs.com. Accessed October 23, 2017 at https://www.drugs.com/history/kte-c19.html Kite Pharma. Pipeline. Accessed April 23, 2017 at http://kitepharma.com/pipeline/ Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory aggressive diffuse large B-cell lymphoma (DLBCL): results from the international SCHOLAR-1 study. Presented at: the 2016 American Society of Clinical Oncology Annual Meeting; Chicago, Illinois; June 3-7, 2016. Abstract 7516. Kite Pharma Reports 82 Percent of Patients Achieved Complete Remission in Preliminary Analysis from Phase 1 ZUMA-3 and ZUMA-4 Trials of KTE-C19 in Adult and Pediatric Patients with High Burden Relapsed/Refractory Acute Lymphoblastic Leukemia. Clinical Trials. Drugs.com. Dec. 4, 2016. Accessed October 23, 2017 at https://www.drugs.com/clinical_trials/kite-pharma-reports-82-percent-patients-achieved-complete-remission-preliminary-analysis-phase-1-17393.html Leukemia and Lymphoma Society. NHL Subtypes. Accessed October 23, 2017 at https://www.lls.org/lymphoma/non-hodgkin-lymphoma/diagnosis/nhl-subtypes Cancer.net. Lymphoma: Non-Hodgkin: Subtypes. Accessed May 2, 2017 at http://www.cancer.net/cancer-types/lymphoma-non-hodgkin/subtypes Clinical Oncology News. How I Manage: Transformed Follicular Lymphoma. Leukemia and Lymphoma Society. Acute Lymphoblastic Leukemia. Treatment. Accessed October 23, 2017 at https://www.lls.org/leukemia/acute-lymphoblastic-leukemia/treatment Kite Pharma Initiates Phase 2 Clinical Study of KTE-C19 (ZUMA-2) in Patients With Relapsed or Refractory Mantle Cell Lymphoma (r/r MCL) to Support Registration for a Second Indication. Press Release, Kite Pharma. March 9, 2015. Accessed October 23, 2017 at http://ir.kitepharma.com/releasedetail.cfm?releaseid=941501 Kite Pharma Details KTE-C19 Launch Preparedness and Near-Term, Next Generation CAR/TCR Product Candidates at Investor Day. Press Release, Kite Pharma. October 19, 2016. Accessed October 23, 2017.} FDA Consumer Updates Depression: FDA-Approved Medications May Help Dealing with ADHD: What You Need to Know Making Decisions for Your Health: Getting the Info You Need FDA: Cutting-Edge Technology Sheds Light on Antibiotic Resistance More FDA updates} } really apt
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