TCell Therapy The Basics Jennifer Mann MSN ANPBC AOCNP Nurse Practitioner Immunotherapy Team Surgery Branch November 21 2019 What are CAR T Cells Chimeric Antigen Receptor CAR T cells T cells that are modified to express a CAR complex ID: 1042319
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1. Chimeric Antigen Receptor T-Cell Therapy:The BasicsJennifer Mann MSN, ANP-BC, AOCNP ®Nurse PractitionerImmunotherapy Team – Surgery BranchNovember 21, 2019
2. What are CAR T Cells?Chimeric Antigen Receptor (CAR) T cells: T cells that are modified to express a CAR complexCAR: immunoreceptor engineered from different sourcesA CAR is derived from a monoclonal antibody used to recognize a specific target
3. Chimeric Antigen Receptors (CARs) Kochenderfer, J. N. & Rosenberg, S. A. (2013)Nat. Rev. Clin. Oncol.
4. How are CAR T Cells Made?
5. Introduction to Chimeric Antigen Receptors Kochenderfer, J. N. & Rosenberg, S. A. (2013)Nat. Rev. Clin. Oncol.
6. Types of CAR T CellsDifferent CAR T cells target different specific surface proteinsThe targeted protein must be expressed by the cancerThe targeted protein must NOT be also expressed somewhere in the body that could cause harmTargeted surface protein examples:DiseaseCD30Hodgkin lymphomaBCMAMultiple myelomaSLAMF7Multiple myelomaCD19Lymphoma and ALL
7. FDA Approval8/2017 – First FDA approved CAR T-cell therapy targeting CD19 for children and young adults with ALL Tisagenlecleucel (Kymriah™)10/2017 FDA approval of anti-CD19 for relapsed DLBCL axicabtagene ciloleucel (Yescarta™)5/2018 FDA approval of Kymriah™ for non-Hodgkin lymphoma??? anti-BCMA CAR next
8. CAR T-Cell Immunotherapy Protocol SchemaEligibility confirmation visit (screening visit)ApheresisCell production and culture expansionBaseline evaluationLymphodepleting chemotherapy conditioningInpatient admissionCAR T-cell infusionInpatient monitoring for toxicitiesLocal outpatient monitoring for toxicitiesDisease evaluation
9. Active Surgery Branch CAR T-cell trialsProtocolTargetMalignanciesNotes10-c-0054CD19B-cell malignancies (ALL, NHL)Allo- CAR18-c-0125BCMAMultiple Myelomafully human, heavy chain only19-c-0102SLAMF7Multiple Myelomaincorporates suicide gene20-c-0008CD19 and CD20Hodgkin and Non-Hodgkin Lymphoma
10. Days -5 to -3cyclophosphamideadministrationDays -5 to -3 fludarabineadministrationDay 0infusion ofCAR transducedT cellsCyclophosphamide: 300 mg/m2 daily for 3 days Fludarabine: 30 mg/m2 daily for 3 days CAR clinical protocol design This chemotherapy is givenin the day hospital
11. CAR T cells can cause severe toxicitiesCytokine release syndrome (“CRS”)Symptoms similar to sepsis due to infection or severe flu-like syndromeHigh feversTachycardiaHypoxiaHypotensionDecrease in liver or kidney functionProlonged PTT and risk of bleedingPatients frequently require ICU admissionUsually occur in first 2 weeks but may occur a month following cell infusion
12. CAR T cells can cause severe toxicitiesNeurologic ToxicitiesConfusionSomnolenceTremorsGait instabilityAphasia, other difficulties speakingSeizuresNeurologic toxicities may occur separately from CRS
13. CAR T cells can cause severe toxicitiesLee et al., Blood 2014
14. Toxicity risk factorsDisease type: ALL vs NHLBone marrow involvementBurden of diseaseType of lymphodepletion chemo (fludarabine?)Cell doseCostimulatory domain?/structure of CAR
15. Toxicity Management: supportive care for CRSToxicityPreventive/supportive measureFeversAcetaminophenCooling blanketsAvoid NSAIDs, steroids and meperidineCardiovascularAt least q 4 hour vitals, q 2 if HR > 115IV fluid boluses for hypotension if SBP < 80% baseline and < 100 mm Hg; or if SBP < 85 mm HgIVF to replace insensible losses; keep net positiveECG, troponin, and Echo if patients require > 1 fluid bolus for hypotension or are in the ICUIDBactrim and acyclovir prophylaxisPan-culture for any feverPan-culture and broad spectrum antibiotics for neutropenic feverHemeAllopurinol for tumor lysis syndrome prophylaxisGoals: Hb > 8, platelets > 20, ANC > 500 (with filgrastim)Goals: PTT normal; give FFP if > 1.5 x ULN; give cryoprecipitate for goal fibrinogen > 100. NeurologicNeurology consult for all patientsBrain MRI and lumbar puncture whenever possible
16. Toxicity management algorithm
17. Outpatient management post CAR T-cellsNeed for frequent labs drawsGCSF support for post-CAR cytopeniasTransfusionsMonitor for delayed CRS and neurological toxicitiesInfectious complications
18. Eligibility – who are we looking for?Must have the type of cancer the CAR T-cell targetProgression or relapse disease through standard therapyNeed to have measurable diseaseThe patient’s cancer must express the targeted surface proteinAble to tolerate apheresis (hemoglobin/platelets)Good performance status Good organ function
19. Other considerationsTiming – patients need to be off therapy for apheresis and prior to treatmentLimited apheresis or cell production slotsMaintain regular contact with home oncologistSocial – costly travel, time off work, caregiver support
20. Thank you!Questions?