IMMUNE EFFECTOR CELLS: CAR T AND OTHER CYTOTOXIC EFFECTOR CELLS OF THE IMMUNE SYSTEM

Transcription

1 IMMUNE EFFECTOR CELLS: CAR T AND OTHER CYTOTOXIC EFFECTOR CELLS OF THE IMMUNE SYSTEM Jennifer Peterson MSN, RN, OCN, BMTCN Jennifer Shamai MS, RN, AOCNS, BMTCN How the Experts Treat Hematologic Malignancies Las Vegas, NV March 15, 2018

2 Disclosures We have nothing to disclose.

3 Objectives Review basics of immunology and immunotherapy Introduce use of CAR T-cells in immunotherapy Present FDA approved CAR T-cell therapies Discuss monitoring for side effects and managing toxicities Introduce regulatory standards of immune effector cells Discuss future directions of immune effector cell therapy Review educational resources

4 The Immune System A complex network of proteins, cells, tissues, and organs aimed at defending the body against infections and other diseases 1) Distinguish self from non-self 2) Identify, target, and eliminate foreign invader Major organs Bone marrow: production of immune cells Thymus: education of immune cells Lymph nodes: immune responses are produced Spleen: immune responses and cell recycling

5 Types of Immunity Innate Immunity Early response Non-specific No immunological memory Adaptive Immunity Naturally or artificially acquired Pathogen and antigen specific Immunologic memory

6 Cells of the Immune System Dendritic cell "Commanders-in-Chief" Present antigen to T-cell Serve as gateway between the innate and adaptive Determine whether to initiate an immune response B-Cells "Artillery" Antigen-specific production of antibodies Help propagate immune response through antigen presentation and ctyokine production Phagocytes "Auxillary Support" Big eaters, cytotoxic Sample the environment Key regulators of wound repair and resolving immune response NK Cells "Special Forces" Early responders, cytolytic, activate immune system Kill tumor cells without prior activation Sense altered "self" T-Cells "Soldiers" Ag-specific killing Orchestrate immune response through direct killing and cytokine release CD4+ = cytokine release, recognize MHC Class II CD8+ = direct killing and recognize MHC Class 1

7 Immune Response (Clark &Kupper, 2005)

8 Immunologic Memory Effector T-cells and antibodies persist for weeks to years after exposure to an antigen (protective immunity) Second exposure to the same antigen produces a much faster response (immunologic immunity)

9 The Immune System and Cancer If cancer is derived from one s own cells, how does the immune system distinguish self (healthy, normal, uninfected cells) from non-self (cancer cells)? How do cancer cells evade and suppress the immune system? How can we combat these mechanisms? How can we boost the immune system?

10 Hallmarks of Cancer Mechanisms of Immune Evasion 1. Defective antigen presentation 2. Induction of tolerance 3. Suppression in tumor microenvironment (Hanahan & Weinberg, 2011)

11 Cancer Treatment Modalities Foundation of cancer therapy for many years: Surgery Chemotherapy Radiation therapy Newer therapies: Targeted therapies Immunotherapy

12 Immunotherapy, the Fifth Pillar Immunotherapy is an approach of harnessing a patient's own immune system to fight cancer Advantages Human immune system can distinguish between healthy and unhealthy cells Safety profiles that are more manageable or mild than traditional therapies Immunotherapy treatment can be dynamic and react to cancer cells as they develop, leading to more lasting results Strategies: cancer vaccines, oncolytic viruses, adoptive transfer of T and NK cells, antibodies or proteins that effect the immune checkpoint pathways

13 Adoptive T-Cell Therapy Exploits the antitumor properties of lymphocytes 1. Lymphocytes are isolated from the patient 2. Expanded ex-vivo 3. Reinfused back into the patient Why use T-cells? Ability to specifically target tumor cells that express small peptides Potentially long clonal lifespan Potential significant expansion in vivo

14 Adoptive T-Cell Therapy 1. Tumor infiltrating lymphocytes (TILs) 2. T-cell specific receptors (TCR) 3. Chimeric antigen receptor T cells (CAR T) (Perica, Varela, Oelke & Schneck, 2015)

15 History of Immunotherapy and Adoptive Cell Therapy 1950s Adoptive immunity first described 1950s-1960s Development of allogeneic HSCT 1970s Graft versus leukemia effect established 1988 Earliest trials using TILs 1989 First CAR T was conceived and developed 2010 First successful CAR T-cell therapy 2010 First cancer vaccine Sipuleucel-T approved 2017 Two CAR T-cell therapies were approved

16 CAR T-Cell Therapy

17 CAR T-Cell Structure

18 CAR T- Cells for Hematologic Malignancies FDA approved products for B-cell malignancies in 2017 Tisagenlecleuel (Kymriah ) indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse Axicabtagene ciloleucel (Yescarta ) indicated for non- Hodgkin lymphoma: Diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma and transformed follicular lymphoma

19 Cell Collection and Lymphodepletion Cell collection via leukopheresis Cell manufacturing Viral vector and chimeric antigen receptors Lymphodepletion Fludarabine and cyclophosphamide Yescarta : fludarabine and cyclophospahmide administered on the fifth, fourth and third day prior to T-cell infusion Kymriah : fludarabine for 4 days and cyclophosphamide for 2 days starting with the first dose of fludarabine Infuse Kymriah 2 to 14 days after completion of the lymphodepleting chemotherapy

20 Response to Therapy Response rates in clinical trials for B-cell ALL were reported as 70-93% complete response and 60-86% complete molecular response Response rates in clinical trials for lymphoma were reported as 82% complete or partial response, with 54% of patients achieving complete response Multifactorial: Tumor type Cell dose infused Design of the chimeric antigen receptor (CAR) Pre-infusion conditioning regimen Relapse: Loss of CD-19 expression of the malignant cells was noted Davila, M., 2017

21 Monitoring and Managing Toxicities of CAR T-Cell Therapy Cytokine release syndrome (CRS)-boxed warning for both FDA approved CAR T-cells Neurologic toxicities-boxed warning for both FDA approved CAR T-cells Other potential side effects

22 Cytokine Release Syndrome Associated with Monoclonal antibody infusion Bi-specific antibodies for leukemia Haploidentical stem cell transplant CAR T-cell therapy Occurs when large number of lymphocytes and/or macrophages are activated and release cytokines that activate other immune cells Interleukin (IL) 6, tumor necrosis factor, IL-2, IL-8 and IL- 10 levels are elevated C-reactive protein and ferritin levels used as markers Lee et al., 2014

23 Cytokine Release Syndrome Onset and severity depend on causative agent and degree of immune cell activation Incidence and severity greater with larger disease burden Primary anticipated side effect after T-cell therapy Occurs in approximately 90% of patients receiving CAR T- cell therapy Can range from mild to life threatening Indicator of response to therapy Fever is the hallmark sign Monitoring is crucial Callahan, C., Baniewicz, D., and Ely, B., 2017

24 Symptoms of Cytokine Release Syndrome Fever-often mimics infection Cardiac Respiratory Neuro Renal Hepatic Gastrointestinal Coagulopathies

25 CRS toxicities by organ system by American Society of Hematology Used with permission. Jennifer N. Brudno, and James N. Kochenderfer Blood 2016;127:

26 Grading Scale for Cytokine Release Syndrome Grade Grade 1 Grade 2 Grade 3 Grade 4 Toxicity Symptoms are not life threatening and require symptomatic treatment for management Fever, nausea, fatigue, headache, muscle pain, malaise Symptoms require and respond to moderate interventions Oxygen requirement < 40% Hypotension responsive to fluids or single, low dose vasopressor Grade 2 organ toxicity Symptoms require and respond to aggressive intervention Oxygen requirement 40% Hypotension requires high dose or multiple vasopressors Grade 3 organ toxicity or grade 4 transaminitis Life-threatening symptoms Requirement for ventilator support Grade 4 organ toxicity Grade 5 Death Lee et al., 2014

27 CRS Grading Assessment and Treatment Grade 1 CRS Fever ( 38.3) Constitutional symptoms Grade 2 CRS Hypotension: responds to fluids or one low dose vasopressor Hypoxia: responds to < 40% O2 Organ toxicity: grade 2 Grade 3 CRS Hypotension: requires multiple or high dose vasopressors Hypoxia: requires 40% O2 Organ toxicity: grade 3, grade 4 transaminitis Grade 4 CRS Mechanical ventilation Organ toxicity: grade 4, excluding transaminitis Extensive comorbidities or older age? No Yes Diligent supportive care Rule out infection Diligent supportive care Monitor cardiac and organ function Diligent supportive care Tocilizumab +/- corticosteroids Lee et al., 2014

28 Neurotoxicity Changes may be subtle Symptoms can range from mild to severe May occur with CRS symptoms or independent of CRS symptoms Pathogenesis unclear Education for patient and caregivers is essential Bayer et al., 2017

29 Neurotoxicity Symptoms may include: Word finding difficulty/aphasia Seizures Tremors Obtundation Headaches Confusion/altered mental status Altered gait Lee et al., 2014

30 Management of Neurotoxicity Neurology consult Rule out other causes with imaging Seizure prophylaxis Immunosuppression with dexamethasone is standard treatment May depend on concurrent CRS present or not

31 Treatment of CRS and Neurotoxicity Monitoring and treatment may require higher level of care Dependant on grade of CRS Tocilizumab Humanized anti-il-6 monoclonal antibody Corticosteroids Siltuximab

32 Other Potential Side Effects B cell aplasia Target CD-19 Tumor lysis syndrome High tumor burden prior to therapy Graft-Versus-Host Disease Immunologic response Relapsed disease due to short persistence of CAR T-cells and antigen loss Psychosocial effects Relapse/refractory disease Travel to treatment institution Cost for stay (approximately 6 weeks) Callahan, C., Baniewicz, D. and Ely, B., 2017 Smith, L. And Venella, K., 2017

33 Regulatory Requirements Products are restricted to certified healthcare facilities Providers who prescribe, dispense, or administer must be trained regarding the management of CRS and neurotoxicity Facilities must be enrolled and comply with the Risk Evaluation and Mitigation Strategy (REMS) Immediate access to 2 doses of tocilizumab within 2 hours of the infusion

34 FACT Immune Effect Cell (IEC) Standards Why develop IEC standards? Novel therapy with unique toxicity profile Administration requires significant collaboration with various members of the healthcare team Coordination of therapy requires a robust clinical infrastructure Maus & Nikiforow, 2017

35 FACT Immune Effector Cell (IEC) Standards New standards and an accreditation program for IECs published early 2017 Cells used to modulate, elicit, or mitigate an immune response for therapeutic intent Includes dendritic, NK, T or B cells Standards apply to the process, not the science Donor workup, apheresis collection, labeling, storage, documentation, product administration, and chain of custody Quality management program Education Maus & Nikiforow, 2017l; Nikiforow, n.d.; FACT, 2017

36 FACT Immune Effect Cell (IEC) Standards Pharmacies shall have access to medications adequate to treat expected complications of EICs, including CRS Training and competency for nurses, APPs, and physicians shall include CRS Tumor lysis syndrome Cardiac dysfunction Respiratory distress Neurologic toxicity Renal and hepatic failure Disseminated intravascular coagulation Anaphylaxis FACT, 2017

37 FACT Immune Effect Cell (IEC) Standards Procedures shall include: Written policies for the detection and management of complications, including CRS and neurotoxicity Process for rapid escalation of care Timely communication to clinical staff, intensive care units, emergency departments and pharmacies Clinical program shall have written guidelines for management of complications FACT, 2017

38 Other Considerations Establishing standards of care Capturing the acuity level of care to adjust staffing levels Creating documentation forms for clinical care, care plans, and patient education Halton, Llerandi, Diamonte, Guintanilla & Maile-Mayer, 2017

39 At What Cost? Tisagenlecleucel: $475,000 Axicabtagene ciloleucel: $373,000 Tocilizumab: ~$4,800 per dose

40 Future Directions in Immune Effector Cell Therapy Other diseases Hematology: Multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia Solid tumors: Glioblastoma, pancreatic, lung, malignant mesothelioma, and prostate (lethal neuroendocrine prostate cancer) Dual target therapy: CD-19 and CD-22 for ALL and CD-33 and CD-123 for AML Allogeneic CAR T-cells for patients who are at high risk for relapse or who relapse post stem cell transplant Universal CAR T-cells

41 Future Directions in Immune Effector Cell Therapy Tumor- infiltrating lymphocytes Advanced colorectal cancer, liver cancer and melanoma T-cell receptors Demonstrating positive results in melanoma and sarcoma Virus specific T-cells Epstein-Barr, adenovirus, cytomegalovirus, BK virus and human herpes virus 6 Bi-specific antibodies Tzannou, I. et al.,

42 Future Directions in Immune Effector Cell Therapy As of 2/2/18: Open T-cell based cellular therapy clinical trials around the world: ~2,345 Open NK-cell based cellular therapy clinical trials around the world: ~300 Clinicaltrials.gov

43 Resources Nurse resources Oncology Nursing Society CAR T-cell Therapy: The Nurse s Role in Treating Patients CE contact hours Society for Immunotherapy of Cancer (SITC)

44 Resources Patient resources National Cancer Institute Leukemia and Lymphoma Society Video: International Myeloma Foundation American Cancer Society Kite Kite Konnect program Novartis Kymriah Cares program