T cell Therapy basics

1. Chimeric Antigen Receptor
T-Cell Therapy:
The Basics
Jennifer Mann MSN, ANP-BC, AOCNP ®
Nurse Practitioner
Immunotherapy Team – Surgery Branch
November 21, 2019

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What are CART Cells?
• Chimeric Antigen Receptor (CAR)
T cells:T cells that are modified
to express a CAR complex
• CAR: immunoreceptor
engineered from different sources
• A 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.

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How are CART Cells Made?
Administration
Cells are infused into the patient
Conservation
Cells are purified and cryopreserved (can be a fresh infusion)
Cell Expansion
Cells are in culture, allowing them to expand and proliferate
Transfection
A gene is inserted using a virus that causes the CAR to be expressed by theT cell
Activation ofT cell
T cells are transformed into cytotoxicT cells
Apheresis
T cells are isolated and collected from the patient's peripheral blood (leukapheresis)

5. Introduction to ChimericAntigen Receptors
Kochenderfer, J. N. & Rosenberg, S. A. (2013)
Nat. Rev. Clin. Oncol.

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Types of CART Cells
• Different CART cells target different specific surface proteins
• The targeted protein must be expressed by the cancer
• The targeted protein must NOT be also expressed
somewhere in the body that could cause harm
• Targeted surface protein examples:
Disease
CD30 Hodgkin lymphoma
BCMA Multiple myeloma
SLAMF7 Multiple myeloma
CD19 Lymphoma and ALL

7. FDA Approval
• 8/2017 – First FDA approved CART-cell therapy targeting CD19 for children
and young adults with ALLTisagenlecleucel (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

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CART-Cell Immunotherapy Protocol
Schema
• Eligibility confirmation visit (screening visit)
• Apheresis
• Cell production and culture expansion
• Baseline evaluation
• Lymphodepleting chemotherapy conditioning
• Inpatient admission
• CART-cell infusion
• Inpatient monitoring for toxicities
• Local outpatient monitoring for toxicities
• Disease evaluation

9. Active Surgery Branch CART-cell trials
Protocol Target Malignancies Notes
10-c-0054 CD19 B-cell
malignancies
(ALL, NHL)
Allo- CAR
18-c-0125 BCMA Multiple
Myeloma
fully human,
heavy chain
only
19-c-0102 SLAMF7 Multiple
Myeloma
incorporates
suicide gene
20-c-0008 CD19 and CD20Hodgkin and
Non-Hodgkin
Lymphoma

10. Days -5 to -3
cyclophosphamide
administration
Days -5 to -3 fludarabine
administration
Day 0
infusion of
CAR transduced
T cells
Cyclophosphamide: 300 mg/m2 daily for 3 days
Fludarabine: 30 mg/m2 daily for 3 days
CAR clinical protocol design
This chemotherapy is given
in the day hospital

11. CART cells can cause severe toxicities
• Cytokine release syndrome (“CRS”)
 Symptoms similar to sepsis due to infection or severe flu-like syndrome
 High fevers
 Tachycardia
 Hypoxia
 Hypotension
 Decrease in liver or kidney function
 Prolonged PTT and risk of bleeding
 Patients frequently require ICU admission
 Usually occur in first 2 weeks but may occur a month following cell
infusion

12. CART cells can cause severe toxicities
• NeurologicToxicities
 Confusion
 Somnolence
 Tremors
 Gait instability
 Aphasia, other difficulties speaking
 Seizures
 Neurologic toxicities may occur separately from CRS

13. CART cells can cause severe toxicities
Lee et al., Blood 2014

14. Toxicity risk factors
• Disease type: ALL vs NHL
• Bone marrow involvement
• Burden of disease
• Type of lymphodepletion chemo (fludarabine?)
• Cell dose
• Costimulatory domain?/structure of CAR

15. Toxicity Management: supportive care for CRS
Toxicity Preventive/supportive measure
Fevers • Acetaminophen
• Cooling blankets
• Avoid NSAIDs, steroids and meperidine
Cardiovascular • At least q 4 hour vitals, q 2 if HR > 115
• IV fluid boluses for hypotension if SBP < 80% baseline and < 100 mm Hg; or
if SBP < 85 mm Hg
• IVF to replace insensible losses; keep net positive
• ECG, troponin, and Echo if patients require > 1 fluid bolus for hypotension or
are in the ICU
ID • Bactrim and acyclovir prophylaxis
• Pan-culture for any fever
• Pan-culture and broad spectrum antibiotics for neutropenic fever
Heme • Allopurinol for tumor lysis syndrome prophylaxis
• Goals: Hb > 8, platelets > 20, ANC > 500 (with filgrastim)
• Goals: PTT normal; give FFP if > 1.5 x ULN; give cryoprecipitate for goal
fibrinogen > 100.
Neurologic • Neurology consult for all patients
• Brain MRI and lumbar puncture whenever possible

16. Toxicity management algorithm

17. Outpatient management post CART-cells
• Need for frequent labs draws
• GCSF support for post-CAR cytopenias
• Transfusions
• Monitor for delayed CRS and neurological toxicities
• Infectious complications

18. Eligibility – who are we looking for?
• Must have the type of cancer the CART-cell target
• Progression or relapse disease through standard therapy
• Need to have measurable disease
• The patient’s cancer must express the targeted surface protein
• Able to tolerate apheresis (hemoglobin/platelets)
• Good performance status
• Good organ function

19. Other considerations
• Timing – patients need to be off therapy for apheresis and prior to
treatment
• Limited apheresis or cell production slots
• Maintain regular contact with home oncologist
• Social – costly travel, time off work, caregiver support

20. Thank you!
Questions?