Immunotherapy: How CAR-T Cellular Therapy Works for …...Development of CAR T-cells First CAR was developed in 1989; this lead to an increased interest in adoptive cellular immunotherapies

Immunotherapy: How CAR T-Cell Therapy Works for Cancer Treatment

Linda Schroeder

RN, MS, AOCNS

University of Chicago Medicine

April 2017

Learning Objectives

• Identify implications for the use of CAR T-cell therapy for

treatment of leukemia and lymphoma.

• Understand the process of how CAR T-cell treatment is

administered.

• Describe the major toxicities and patient care guidelines

for CAR T-cell treatment.

• Outline education guidelines for patients undergoing CAR

T-cell therapy and for their families/caregivers.

2CAR T-cell April 2017

January 30, 2017


Definition

Chimeric antigen receptor (CAR) T cells

T-lymphocytes that have a gene inserted that expresses CARs. The CARs are proteins that recognize and destroy antigens on the surface of cancer cells.

CAR T-cell therapy is a type of targeted immunotherapy that uses tumor-specific antigen recognition.

https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy


Goals of Treatment for SCT

Autologous stem cell transplant

• High dose chemotherapy

• Stem cells are infused to ‘rescue’ or re-seed the bone marrow

Allogeneic stem cell transplant

• Conditioning chemotherapy used to weaken the patient’s own immune system and make space

for donor stem cells to engraft

• Donor’s immune system to prevent disease relapse

CAR T-cell therapy

• Autologous T-lymphocytes genetically modified and expanded are infused to target cancer cells


Development of CAR T-cells

First CAR was developed in 1989; this lead to an increased interest in adoptive

cellular immunotherapies.

2nd generation CARs were developed in 1998, which had greater antitumor

response due to co-stimulatory signaling for T-cell activation

CD19-specific CAR for hematologic malignancies was created in 2006

• CD19 is on the surface of B-cells and B-cell malignancies, so anti-CD19 CAR

T-cells were shown to have activity against B-cell ALL and B-cell lymphoma.


University of Chicago Experience in Early Studies

• Novartis 2201 IRB 15-0544 (JULIET)

Phase 2 Trial To Determine The Efficacy And Safety Of CTL019 In Patients With Relapsed Or Refractory Diffuse Large B-Cell Lymphoma

6 patients infused (May –Dec 2016), closed to accrual

• KTE-C19-102 (ZUMA-2) open currently

Phase 2 Study Evaluating the Efficacy of KTE-C19 in Subjects with Relapsed/Refractory Mantle Cell Lymphoma

• KTE-C19-103 (ZUMA-3) open currently

Phase 1/2 Study Evaluating the Safety and Efficacy of KTE-C19 in Subjects with Relapsed/Refractory B- Acute Lymphoblastic Leukemia

• Juno (Rocket)

Phase 2 Trial to Determine the Efficacy and Safety of JCAR015 in Subjects with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

One patient infused, had severe CRS and neurotoxicity; study terminated for safety reasons.



CAR T-cell April 2017 9



Phases of Treatment in CAR T-cell therapy

1. Screening and staging

• Review of eligibility (organ function, ?active infections)

2. Leukapheresis

• scheduling coordinated with apheresis unit and with sponsor/manufacturing site

• cells shipped by courier for manufacturing and expansion (2-3 weeks)

3. Possible bridging chemotherapy

4. Lymphodepleting (LD) chemotherapy: Fludarabine and Cytoxan


5. Central line placement, admission to hospital, CAR T-cell infusion

• Cells arrive by courier, frozen

• Premeds given for infusion: tylenol and benadryl (NO steroids)

• Inpatient stay 2-3 weeks

• Local housing after hospital discharge

6. Follow-up monitoring, restaging

• Return home ~4-5 weeks after infusion, with monthly follow-up visits



.


Possible Toxicities

• Infusion reactions: fever, chills, nausea

• Tumor lysis syndrome

• Cytokine Release Syndrome (CRS)

Symptoms may include high fevers, rigors, myalgias/arthralgias,

nausea/vomiting/anorexia, headache, hypotension, dyspnea,

tachypnea, hypoxia

• Fever and neutropenia


Toxicities

• Neurologic toxicity

delirium

encephalopathy

aphasia

seizures

Neurologic symptoms are reversible and can occur independent of CRS.

• B cell aplasia, may require IVIG infusions


CRS definition

CRS is a symptom complex associated with therapies that activate lymphocytes. It results from release of cytokines and activated immune cells, causing a high level of immune activation.

– Potentially life-threatening

– Symptoms and severity varies, features mimic infection

– Signs and symptoms may include: constitutional (fevers, rigors, myalgias),rash, GI, hypoxemia, tachycardia, hypotension, altered coagulation, renal (azotemia), hepatic, neurologic

– Can be reversed (or prevented) by infusing Tocilizumab, which is an immunosuppressive therapy that blocks IL-6


CRS signs and symptoms by organ system


CRS grading scale


CRS Algorithm

• Grade 1 CRS (mild)

– Oxygen

– Fluids

– Low dose vasopressor support

– Antipyretics

– Monitor/manage complications of tumor lysis syndrome

– Consider antibiotics if patient is neutropenic

• Grade 2,3, or 4 CRS (moderate to severe)

– Tocilizumab

– Dexamethasone

– If no improvement in 12-18 hours, repeat 2nd dose tocilizumab


Management guidelines: staff

• Educate transplant nurses, ICU staff, support staff, and ED staff on CAR T-cell therapy, monitoring toxicities inpatient and outpatient, managing acute and chronic complications

• Obtain insurance approval

• Communicate with patient’s local oncologist

• Provide support and education for caregivers; collaborate with social workers

• Prepare patient for lengthy process, possible outcomes

• Prepare educational tools for patients

• Knowledge of and adherence to protocols

• Educate on the use of the CRS algorithm


Management guidelines: patient and caregiver

• Educate patient on the treatment process, risks, consent, concomitant medications

• Give patient a calendar with scheduled and/or projected treatment dates

• Assist is planning for local lodging

• Identify additional resources if needed

• Explain caregiver role and encourage patient to arrange for backup caregiver(s)

• Standard infection prophylaxis with Bactrim, Acyclovir, and Voriconazole

• G-CSF if indicated

• ID card; instruct on methods for communicating with providers; who and when to call with questions or concerns

• Need for long-term follow-up


Resources: LLS fact sheet


Discovercart.com


DLBCL Case Study

53 y/o male, relapsed/refractory DLBCL, diagnosed stage IIIA disease

November/2013, treated with R-CHOP X 6 cycles

June 2014: had an initial response by PET, but by the end of treatment, scans

showed 2 areas of uptake (biopsy R axillary LN negative, but L inguinal lesion grew over the

summer and biopsy confirmed recurrence in October 2014)

Nov 2014: R-ICE X 3, followed by decreased uptake by PET, persistent disease R

axilla and L groin

Jan 2015: Stem cell mobilization and collection

PET/CT shows further interval decrease in size and metabolic activity


Feb 2015: BEAM conditioning and autologous SCT

April 2015: L inguinal lump, PET inconclusive, biopsy confirms relapsed DLBCL

June 2015: worsening L groin LAD, Selinexor trial

July 2015: progressive disease, admitted for fevers, worsening L groin wound

Ibrutinib/Lenolidomide trial

Oct 2015: PD, admitted for R-methotrexate/cytarabine

Completes 2 cycles, followed by XRT to L groin

Jan 2016: responding to XRT, plan for CAR-T Novartis trial, apheresis


Feb 2016: near complete CR, but multiple pulmonary lesions

April 2016: completed 2 cycles Gem/Ox (bridging chemo)

May 2016: Fly/Cy (LD chemo) followed by CAR T-cell infusion

high fevers, confusion (word-finding difficulty), tremors; symptoms resolved and

discharged 19 days after infusion

At f/u clinic visits, noted to be neutropenic and thrombocytopenic, thought to be

due to Flu/Cy

Feb 2017, 9 months post CAR T-cell infusion, blood counts improved, PET scan

remains negative, patient is working full-time


Summary

• CAR T-cell therapy is a new approach that harnesses a patient’s own immune

system to fight B-cell malignancies. Durable remissions have been achieved,

and prognosis has been shown to be good for patients who maintain CR for 6

months.

• Patient must also be worked up for infection when symptoms of CRS occur.

• CRS and neurologic events associated with CAR T-cell therapy are usually

manageable and reversible.

• Patients need to be monitored for toxicities long-term as knowledge continues

to be developed.



Future Directions…..???

• How to sustain remission post-CAR T therapy:

allogeneic transplant?

booster CAR T-cell infusion?

• How to treat post-CAR T-cell relapse:

reinfusion?

stem cell transplant?

targeted therapies, such as durvalumab

• Donor CAR T-cells for patients who cannot get sufficient numbers of cells manufactured?

• Expanded use for other heme malignancies


Thank you to our SCT TeamApheresis staff Clinical Cell Processing Lab Administration

JoAnn Allen, RN Guadalupe Martinez Aaron Chrisman

Michelle McCarter, RN Denise Torres Mylove Mortel, RN

Veronica Placencia Elingel Aguada, RN

Jill Bastedo, RN

Research Nurse Coordinators Clinical Research Coordinators

Sadi Dixon, RN John Tyson

Linley Moreland, RN Alexis Small Social Workers

Yolanda Barnes, RN Ray Robinson Marc Paloma, LCSW

Rebecca Malloy, RN Timothy McNichol, LCSW

Physicians Nurse Practictioners

Michael Bishop, MD Jean Ridgeway, RN Other support

Wendy Stock, MD Katherine Cappitelli, RN Carmalita Collier

Satyajit Kosuri, MD Keriann Kordas, RN Debbie Saucedo

Sonali Smith, MD Alice Choi, RN Glenna Smith

Justin Kline, MD Kassandra Carreri, RN Sandeep Parsad, PharmD

Peter Riedell, MD Emily Bauer, RN

Kaitlin Holcomb, RN32CAR T-cell April 2017

Questions?

[email protected]


University of Chicago Center for Care and Discovery


Documents

Immunotherapy: How CAR-T Cellular Therapy Works for …...Development of CAR T-cells First CAR was developed in 1989; this lead to an increased interest in adoptive cellular immunotherapies