1. Targets of CAR-T Targets of CAR-T Therapy Quality recombinant proteins you can count on! “

2. Contents https://www.creativebiomart.net  What is CAR-T therapy?  Which cancers can be treated with CAR-T cell therapy?CAR-T cell therapy  The process of CAR-T cell therapy  Structure and Generations of CAR-T Cell  Targets of CAR-T Cell Therapy  CAR-T Cell Therapy Clinical Trial and Side Effect

3. What is CAR-T therapy?

4. T Cells T cells are immune system cells that play several key roles in the body’s fight against the disease. They help the immune system respond to a disease and directly kill diseased cells. CARs Chimeric antigen receptors (CARs)are engineered receptors which graft an arbitrary specificity onto T cell, these receptors are used to graft the specificity of a monoclonal antibody onto a T cell, with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources. What is CAR-T Therapy? https://www.creativebiomart.net CAR T-cell therapy is a type of immunotherapy that changes a patient’s own T cells so they are able to recognize and attack cancer. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added in the laboratory. CAR-T Therapy

5. Cancers can be treated with CAR-TCAR-T

6. 1992 Primary T cell engineering 1993 First- generation CARs(CD3ζ- based) 2002 Second-generation CARs (CD28-based) 2003 Demonstration of CD19 as valid CAR target Second-generation CARs(4-1BB-based ) 2007 First IND for CD19 CAR therapy 2010 First case report of CD19 CAR therapy in NHL 2011 First case report of CD19 CAR therapy in CLL 2013 First case report of CD19 CAR therapy in ALL 2017 FDA approval of CD19 CAR therapy for pediatric for ALL and NHL Cancers can be treated with CAR-T https://www.creativebiomart.net

7. FDA Approved Yescarta has been approved for patients with large B-cell lymphoma that has relapsed or does not respond to standard treatments. Kymriah is for pediatric and young adult patients age 25 or younger with B-cell acute lymphoblastic leukemia. Cancers can be treated with CAR-T https://www.creativebiomart.net To be eligible for either treatment, patients must have been treated unsuccessfully with at least two other cancer therapies.

8. Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful. EGFR, EGFRvIII, IL13Rα2, HER2… Components of the microenvironment that surrounds them conspire to blunt the immune response. ECM  HSPGs  HPSE Obstacles inSolid Tumor Cancers can be treated with CAR-T https://www.creativebiomart.net

9. The process of CAR-T cell therapy

10. Process of CAR-T cell therapy https://www.creativebiomart.net 06 01 02 03 04 05 Collected T cell from patient T cell activation Antibody-coated beads Interleukins Viral vector transfects CAR DNA Chimeric Antigen Receptor (CAR) T cell reengineering T cell multiplied Infusion CAR-T cell against recurrence CAR-T Cell Tumor

11. Structure and Generations of CAR-T Cell

12. https://www.creativebiomart.net CD3ζ ITAM

13. Structure and Generations of CAR-T Cell https://www.creativebiomart.net 1st CAR Antigen recognition domain CD3z signaling domain 2nd CAR 3rd CAR 4 th /TRUCK CD28/4-1BB costimulatory signaling domain CD28 4-1BB CTLA-4 PD-1 KIR KIR2DS2 DAP12 Cytokine

14. Targets of CAR-T Cell Therapy

15. https://www.creativebiomart.net TargetCAR structureMalignancy BCMACD3ζ and 41BBMM CD19 CD3ζ and CD28; CD3ζ and 41BB KIR2DS2 and DAP12- Lymphoma; Leukemia CD22CD3ζ and CD28FL; NHL; DLBCL; ALL CD20CD3ζ; CD3ζ and 41BB-CD20positive malignancies CD138CD3ζ and 41BBMM CD33CD3ζ and 41BBAML CD123CD3ζ and CD28AML CD19 CD20 CD3ζ and 41BBLeukemia; Lymphoma CD19 PSMA CD3ζ and CD28 PD-1 or CTLA4 Leukemias FITC-CD19 AbCD3ζ and CD28CD19 positive cancers IgκCD3ζ and CD28CLL LeYCD3ζ and CD28AML ROR1CD3ζ and 41BBCLL; SLL CAR-T-cell targets for the treatment of hematological tumors

16. Targets of CAR-T Cell Therapy https://www.creativebiomart.net TargetCAR structureMalignancy BiotinCD3ζ, CD28 and 41BB EGFRvIII positive cancer CD171 CD3ζ and 4-1BB; CD3ζ, CD28 and 4-1BB Neuroblastoma EGFRvIII CD3ζ and 41BB CD3ζ and ICOS- Glioma FAP CD3ζ and CD28 KIR2DS2 and DAP12- Mesothelioma; Lung cancer FRCD3ζ and CD27 Ovarian cancer; Breast cancer Glypican-3CD3ζ, CD28 and 41BB Hepatocellular carcinoma HER2CD3ζ and CD28 HER2 positive cancer; Sarcoma CAR-T-cell targets for the treatment of solid tumors TargetCAR structureMalignancy HER2 MUC1 CD3ζ and CD28Breast cancer HER2 IL13Rα2 CD3ζ and CD28Glioblastoma IL13Rα2 CD3ζ; CD3ζ and 41BB CD3ζ and CD28 CD3ζ, CD28 and 41BB CD3ζ, CD28 and OX40- Glioma Mesothelin CD3ζ; CD3ζ and CD28 CD3ζand 41BB CD3ζ and ICOS KIR2DS2 and DAP12- Mesothelioma; Pancreatic cancer; Non-small cell lung cancer Mesothelin CD19 CD3ζand 41BBPancreatic cancer MUC1CD3ζ and 41BB MUC1 positive solid tumor

17. CD19 https://www.creativebiomart.net

18. Targets of CAR-T Cell Therapy https://www.creativebiomart.net

19. CD20 https://www.creativebiomart.net

20. BCMA https://www.creativebiomart.net Hodgkin’s lymphomas myeloma cells

21. HER2 https://www.creativebiomart.net

22. CAR-T Cell Therapy Clinical Trial and Side Effect

23. https://www.creativebiomart.net As of August 2017, there were around 200 clinical trials happening globally involving CAR T-Cells. Of those trials, around 65% were trials in which haematological malignancies were explored, and 80% of them involved CD19 CAR T-Cells targeting the B-cell cancers. Studies had begun by 2016 to explore the viability of other antigens such as CD20.

24. CAR-T Cell Therapy Clinical Trial and Side Effect https://www.creativebiomart.net Cytokine-Release Syndrome (CRS) In the case of CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure. CRS symptoms can range from mild flulike symptoms that include nausea, fatigue, headache, chills and fever to more serious symptoms. low blood pressure, tachycardia, capillary leakage, cardiac arrest, cardiac arrhythmias, cardiac failure, hemophagocytic lymphohistiocytosis …

25. CAR-T Cell Therapy Clinical Trial and Side Effect https://www.creativebiomart.net Neurologic Toxicities Language impairment (aphasia), confusion, delirium, involuntary muscle twitching, hallucinations, unresponsiveness or seizures

26. CAR-T Cell Therapy Clinical Trial and Side Effect https://www.creativebiomart.net Neurologic Toxicities B-Cell Aplasia CAR T-cell therapy targeting antigens found on the surface of B cells not only destroys cancerous B cells but also normal B cells. These normal B cells are also often killed by the infused CAR T cells.

27. CAR-T Cell Therapy Clinical Trial and Side Effect https://www.creativebiomart.net Neurologic Toxicities B-Cell Aplasia Tumor Lysis Syndrome (TLS) A group of metabolic complications that can occur due to the breakdown of dying cells - usually at the onset of toxic cancer treatments.

28. CAR-T Cell Therapy Clinical Trial and Side Effect https://www.creativebiomart.net Neurologic Toxicities B-Cell Aplasia Tumor Lysis Syndrome (TLS) Anaphylaxis (Life-threatening Allergic Reaction) Symptoms associated with anaphylaxis include hives, facial swelling, low blood pressure and respiratory distress.

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