Immunotherapy: Current Uses, Toxicity and its Management

Dr Kortnye Smith

July 2018

Overview

• Immunotherapy • Cancer and the Immune System

• History of Immunotherapy

• Anti-CTLA4

• Anti-PD1

• Toxicity • Immune Related Toxicity

• Common Toxicity

• Additional Psychosocial Stress

• Questions

T Cell Activation

Individual human tumours harbour a multitude of somatic mutations and epigenetically dysregulated genes. The products of these gene changes are potentially recognizable as foreign antigens on the surface of the cancer cell. These foreign can be recognized by APC and presented to the T Cells for destruction of the cancer cell. Despite this, the overriding relationship between the immune system and “growing” cancers is one of tolerance, in which, paradoxically foreign molecules expressed by tumour cells are viewed as self.

Immune Response to Tumours 1. Elimination Immune cells able to destroy all cancer cells. 2. Equilibrium Immune cells become unable to eliminate all cancer cells, but may be able to prevent expansion and metastasis: this keeps the tumour at bay produces a static phase called equilibrium. Selection occurs for cancer cells with higher ability to metastasise 3. Escape Over time: dynamic interaction between tumour and immune system result in selection for tumour cells which can escape the immune system clinically detectable tumours

Dunn (2004) Immunity

Tumour Evasion of the Immune System

• Loss of antigenicity

- Acquisition of defects in antigen processing and presentation

- Loss of immunogenic tumour antigens loss of proteins of cell surface to create peptide-MHC complex

• Gain of immunosuppressive properties

- Increased expression of PD-LA

- Secretion of suppressive cytokines (ie. IL-10, TGFB)

• Creating an immunosuppressive environment

• Recruiting immunosuppressive leukocytes

Beatty (2015) Clin Can Research

History of Cancer Immunotherapy

WILLAM COLLEY Tumours can be eliminated in response to bacteria

MACFARLANE BURNET Concept of Cancer Immunosurveillance: tumours can be attacked by immune system

Anti-CTLA4 Ipilimumab

Anti-CTLA4 T Cell Activation

Tumour Cells have foreign antigen/peptide on their surface.

They are surveyed by Antigen Presenting Cells (APC)

APC present the antigen as a MHC/Antigen complex which bind with the T cell receptor (TCR)

Signals from the TCR are then amplified by co-stimulatory molecules (CD28/B7)

This results in T cell proliferations and differentiation allowing for destruction of the tumour cells via lysis

Ribas et al, NEJM 2012

Buchbinder et al. JCI 2015

Anti-CTLA4 T Cell Inhibition

Following activation of the T cell; Cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) is up regulated in the T cell CTLA4 has a much higher affinity for B7 (cf CD28) Approximately 48 hours post T cell activation CTLA4 begins to bind with the B7 molecule on the APC surface in This provides inhibitory signals to the T cells to decrease activity

Anti-CTLA4 Mechanism of Action

Anti-CTLA- 4 (Ipilimumab) is a monoclonal antibody (given IV x4 doses, 3 weeks apart, 3mg/kg) It binds to CTLA-4 when it is expressed on the surface of the T cell CTLA-4 bound to Ipilimumab is then not able to bind with B7, leaving B7 free to continue to bring to CD28 and provide ongoing co-stimulation of the T cell T cell continues to receive activation Signals with ongoing cell lysis and further immune activation

Anti-CTLA4 Summary

Anti CTLA4 provides superior overall survival benefit compared to Chemotherapy in melanoma Lower rates of overall survival and response rate compared with Anti-PD1 agents and combination therapy Median Overall Survival Ipilimumab: (CHECKMATE 067): 19.9 months (95% CI 16.9- 24.6) Toxicity (Immune Related Adverse Events) Grade 3-4 Immune Related Adverse Events *(CHECKMATE 067): 19.6% (11% GI related)

Anti-PD1 and Anti-PDL1 Nivolumab

Pembrolizumab

Avelumab

Atezolizumab

Durvalumab

Cemiplimab

(and more in development)

Role of PD-1 in Cancer and Immune tolerance

PD-1 is a surface co-inhibitory receptor expressed on T cells, B cells, and NK following activation

It has two ligands: PD-L1 and PD-L2, binding to these ligands inhibits T cell receptor signaling and downregulates immune response

Promotes tolerance and prevents tissue damage in the setting of chronic inflammation, promote peripheral tolerance and balance

Many solid tumours express or over express PD ligand 1 (PD-L1)

McDermott (2013) Cancer Med

Anti PD-1 Therapy Mechanism of Action

Cancer cells can upregulate the amount of PD-L1 expressed on the surface of the cell downregulation of the T cell activity using the negative feedback of PD1-PDL1 binding Anti- PD1 Antibodies attach to PD-1 on the circulating T-cells This leaves the ligand unable to bind with PD-L1 and therefore stimulates ongoing immune response Given regularly on an ongoing basis ( different compounds given on different dosing schedules, either mg/kg or flat dosing) Length of treatment not established, possibly 2 years

Anti-PD1 Monotherapy and Efficacy

Increasing number of cancers being treated with Anti-PD1 therapies Efficacy is dependent on immunogenicity of the tumour

Current Clinical Use of Anti-PD1 therapies Current PBS Indicated Current Access Schemes Current Clinical Trials

Melanoma Lung Cancer 1st line thearpy (PDL1 >50%)

Colorectal Cancer

Lung Cancer, 2nd line therapy Cutaneous Squamous Cell Carcinoma

Triple Negative Breast Cancer

Renal Cell Carcinoma, 2nd line therapy

Merkel Cell Carcinoma Upper GI

Hodgkin’s Lymphoma, post transplant

Rare Cancer

Bladder Carcinoma , 2nd line Phase 1

Combination Therapy Ipilimumab + Nivolumab

Combination Therapy • Dual blockade of Checkpoints Inhibitors

CTLA4 and PD-1 inhibit antitumour immunity through complementary and non-redundant mechanisms to downregulate the immune response. The use of the two treatments together shows synergistic improvement in antitumor responses. Dual Blockade for 3 months, followed by up to 2 years of Anti-PD1 therapy

Okazai (2013) Nature Immunology

Long Term Efficacy of Immunotherapy

Long Term Efficacy: 5 year data • Phase I (CA209-003)

Possibility of durable long term responses with Anti-PD1 (in melanoma, other cancers still pending)

34% of patients alive at 5 years

Nivo (3mg/kg) All Nivo doses

12 months 64.7% (37.7-82.3) 62.7% (52.6-71.2)

24 months 47.1% (23.0-68.0) 48.0% (38.1-57.2)

48 months 35.3% (14.5-57.0) 34.8% (25.7- 44.1)

60 months 35.3% (14.5-57.0) 33.6%(24.6-42.9)

mOS 20.3% (7.2-NR) 17.3 (12.5-37.8)

Hodi (2016) AACR

Long Term Overall Response Rate

• The most important finding regarding Ipilimumab from the initial clinical trials is that it has the potential for

• LONG TERM RESPONSE (?CURE)

• 10 year follow up data shows ongoing survivors from metastatic melanoma at 20%

Median Overall Survival 3 year Overall Survival

9.5m (9.0-1.0) 21% (20-22)

Pooled Analysis of 1,861 patients from 12 studies AND expanded access portal 2,985 patients

Schadenorf (2015) JCO

Immunotoxicity

Immune Related Adverse Events Specific Immune Related Adverse Effects

Mechanism of Immunotoxicity

Normal role of the the checkpoints PD-1 and CTLA-4 is to retain balance between activity and quiescence in the immune system. By blocking these checkpoints, Anti-PD1 and Anti-CTLA4 disrupt this balance. This can result in unopposed immune activation and T-cell dysregulation results in inflammation and tissue damage Can occur to ANY tissue in the body, indiscriminate in nature

Yoest (2017) Immunotargets

Immune Related Adverse Events

Subgroup of Adverse Events from Drugs Separate from standard “side effects” More common in some organ types than others - Skin - GI tract - Liver - Endocrine (Thyroid, Adrenal Pituitary) - Lung

Immunotoxicity

Champiat et al. Annals of Oncology 201 Tepley et al. Oncology 2014 Weber et al. JCO 2015

Onset of Symptoms varies, peak time in first 3 months Symptoms can occur at any time including after months of therapy Variables include: - Which immunotherapy used - Underlying immune related

disease - Underlying cancer diagnosis

Rates of Toxicity • Ipi/Nivo > Ipi > Nivo

Ipilimumab • 28% Grade 3 + 4 toxicity Higher rates of: GI involvement Nivolumab • 21% Grade 3 + 4 Toxicity Higher rate of: endocrine Combination Therapy • 59% Grade 3 + 4 toxicity Higher rates of: hepatic ++, lung, multiple concurrent tox

Wolchok (2017) NEJM

Immunotoxicity

Unless there is a good alternative diagnosis for inflammation, symptoms should be considered autoimmune in nature and treated as such.

Most irAE are reversible provided vigilant monitoring and early treatment *excludes most endocrinopathies which are rarely reversible

BMS + Trial Investigators developed protocol-specific treatment guidelines for management of irAE

Management of Immunotoxicity • Generalised Overview of Management

+ Increase monitoring + Rule out non-immune related causes + Look at individual management guidelines for specific toxicities + Involve specialist teams + often very slow wean of steroids over 2-3 months

Medication for Management of Immunotoxicity

First line: • Steroids: oral, IV

Second and additional lines of treatment (with expert advice) • Infliximab • Mycophenolate • Azathioprine • Budesonide • IVIG • Plasmaphoresis • Anti-Thymocyte Globulin

Cutaneous • Most common toxicity from Immunotherapy

Presentation

Most common

• macular papular rash over the trunk and chest

Less common

• Stephen Johnson

• Sweet Syndrome

• Bullous Pemphigoid

Can worsen

• Psorasis

• Lupus

Management

Mild

• Symptomatic

• Localised steroid cream

Moderate

• Systemic sral steroids

Severe

• Supportive care, admission, IV immunosuppression

Rheumatology

Also Flare of Previous Disease (can occur de novo also)

• Polymyalgia Rheumatica

• Myositis

• Rhematoid Arthritis

• Psoriatic Arthritis

• Sjorgens Syndrome

• Inflammatory Arthropathies

• Vasculitis/ Artiritis

• Dermatomyositis

• SLE

Management

Mild

• Symptomatic

• Simple Analgesia

Moderate

• Low dose oral steroids +/- pulse

• Steroid sparing agents

• Try to continue on drugs

Severe

• If multi-organ involvement may need high dose immunosuppression

Colitis • And other additional GI toxicity

Presentation Colitis • Diarrhoea (>4 above

baseline) • PR blood loss/ mucus • Cramping abominal pain

Oesophagitis/ / Gastritis/ Enterocolitis

Management

Exclude infectious cause, C.diff

Mild

• IV fluids, stool chart, hospital admission

Moderate- Severe

• IV methylprednisolone 2mg/kg for 3/7

• Infliximab

• Slow wean of steroids

• Stop drugs

Endocrinopathies • Thyroiditis, Hypophysitis, Adrenalitis

Presentation

Thyroiditis

• Hypo or Hyperthyroidism

Hypophysitis

• Acute, visual change, headache

• Lethargy, fluid/electrolyte imbalance

• Decrease Libido

Adrenalitis

• Lethargy, weight loss, anorexia, nausea fatigue

• Hypotension

Management during treatment

• Regular review of Sx

• Blood tests: thyroid levels, random cortisol

Management

• Determine cause

• Replace hormone

• Will not recover function of endocrine glands with immunosuppression

• Continue immunotherapy

Pneumonitis

Presentation

Imaging Changes

Dry cough

Shortness of breath

Tachypnoea

Management

Exclude radiation change, infection

Mild

• Monitor, reimage and review frequently

Moderate- Severe

• Admit

• Support O2 supplementation and ventilation

• Commence methylprednisilone

Hepatitis

Management

Mild

• Observation

Moderate

• Cease immunotherapy

• Steriod

• Mycophenolate

Presentation

Increased liver function tests

Lethargy

Rare Immunotoxicities • High level of suspicion required

Neurological

- Gullian Barre, Myelopathy, Encephalitis, Myasthenia

- Peripheral Sensory Motor Neuropathy

- Myasthenia Gravis

Blood

• Haemolotyic Anaemia

• Neutropenia

• Activation of CLL

Renal

• Nephritis

Cardiac

- Myositis

Endocrine

• Endocrine Failure of Pancreas: Brittle T1 DM

Renal

• Nephritis

Champiat et al. Annals of Oncology 201

Less reported but common side effects

Fatigue ‘A distressing, persistent, subjective

sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.” NCCN definition 2017

Fatigue affects caregiver and patients QoL Burden of care increases on care givers Minimal effective strategies for managing effects of fatigue

Fatigue

Mechanism not well understood ? Tumor related substances ? Cytokine production ? Muscular/Neuromuscular junction abnormalities

Not well captured on trials, likely under-reported at 20-40%

Psychological Effects and Impact of Treatment

• New concept of long/longer term survival cf an inevitably fatal disease • Challenging to council patients and to gain understanding

• Fear of Cancer Recurrence • Scan related Anxiety • Fear of Second Cancer

• Impact on Work • Cost of treatment, accommodation and travel

Adjuvant Therapy

Adjuvant Therapy in Melanoma • Is not currently standard of care in Australia, not PBS listed

Previous evidence for Inteferon in Stage III disease Stage III disease • High rates of recurrence of melanoma and subsequent

metastatic disease in Stage III disease,

• Aims to decrease disease recurrence post surgical resection

• Disease specific survival (10 year)

• IIIA: 88% • IIIB: 77% • IIIC: 60% • IIID: 24%

Gershenwald (2017) CA

Adjuvant Immunotherapy Summary • Very active space

Inteferon is currently PBS approved in Australia for treatment of Stage III melanoma.

• Low uptake due to poor OS benefit

• High levels of toxicity

Dabrafenib/Trametinib shows improved OS in BRAF +ve patients

Ipiliumab has shown an overall survival benefit compared to placebo (not inteferon)

Nivolumab has shown improvement in recurrence free survival compared Ipilimumab

• No overall survival benefit reported as yet

Current trial investigating:

• Use of combination Ipilimumab/ Nivolumab vs. Nivolumab

Future Directions

Any questions…