Toxicities and clinical issues with Immunotherapies Reuben Benjamin King’s College Hospital

Overview of emerging Immunotherapies for Myeloma Monoclonal antibodies Checkpoint inhibitors Bispecific T-cell engagers (BiTEs) CARs, TCR therapy Next generation ImiDs (CelMods) Vaccines Allogeneic SCT

Toxicity profile for immunotherapies Distinct toxicity profile compared with chemotherapy Mediated by immune activation Skin : pruritis, rash Gut : colitis Liver : autoimmune hepatitis Endocrine : hypothyroidism Also immune mediated neuropathy, myositis, arthritis, pneumonitis Treatment generally with steroids

Toxicity of checkpoint inhibitors in myeloma Keynote 183 Trial - Pomalidomide/Dex +/- Pembrolizumab for relapsed MM ( >2 lines of therapy) - Number of deaths = 29 (Pembro arm) v 21 (control arm) HR =1.61 at median of 8.1 months - Grade 3-5 toxicity 83% v 65% - SAEs 63% v 46% - ORR 34% v 40%

Toxicity of checkpoint inhibitors in myeloma Keynote 185 Trial - Lenalidomide/Dex +/- Pembrolizumab for upfront treatment of SCT ineligbile MM - Number of deaths = 19 (Pembro arm) v 9 (control arm) HR = 2.06 at median of 6.6 months - Grade 3-5 toxicity 72% v 50% - SAEs 54% v 39% - ORR 64% v 62%

Toxicity of checkpoint inhibitors in myeloma Causes of death in Pembro arm (unrelated to progressive disease) Myocarditis * Stevens-Johnson syndrome * myocardial infarction pericardial hemorrhage cardiac failure respiratory tract infection neutropenic sepsis sepsis multiple organ dysfunction respiratory failure intestinal ischemia * cardio-respiratory arrest Suicide pulmonary embolism cardiac arrest pneumonia sudden death large intestine perforation *

Monoclonal antibodies in myeloma anti-CD38 Daratumumab, Isatuximab, MOR202 anti-CS1 Elotuzumab BiTEs BCMA-CD3 CD138-CD3

Toxicity of monoclonal antibody therapy in myeloma Infusion related reactions 10-71% Haematological 20-28% Interference with laboratory assays M protein Indirect antiglobulin test

Bispecific T cell engager antibodies (BiTEs)

BiTEs for myeloma CD3-BCMA antibody CD3-CD138 antibody Trials ongoing ? Expected toxicity similar to Blinatumomab in B-ALL Infusion reactions Cytokine release syndrome Neurotoxicity Infections

Adoptive T-cell therapy for myeloma CAR T-cell therapy TCR therapy DLI post RIC Allogeneic SCT

Chimeric antigen T cell (CAR-T) therapy

CAR-T cell evolution

CAR-T cell manufacturing process - Autologous CARs - Allogeneic DLI CARs - Off the shelf CARs

Variation in CAR-T cell products Same antigen target but different scFvs Different costimulatory domains CD28, 41BB, 28+41bb Different gene transfer techniques Retroviral v lentiviral v non viral Range of cell manufacturing processes Autologous v Allogeneic (DLI-CAR) v off-the-shelf CARs

CAR-T cell therapy for myeloma BCMA CAR APRIL CAR CS-1 CAR CD19 CAR

Complications of CAR-T therapy Cytokine release syndrome Neurotoxicity Infections Cytopenia GVHD (with allogeneic CARs)

Cytokine release syndrome Occurs in 20-40% of CAR treated patients Fever, malaise, tachycardia, hypotension, capillary leak, renal failure, DIC Severity related to disease burden Elevation of serum cytokines Treatment aggressive supportive care IL-6R blockade (Tociluzumab) Steroids

CRS management

Neurotoxicity Occurs in 30-40% of CAR treated patients Confusion, delirium, aphasia, seizures, coma Pathogenesis likely cytokine mediated Treatment Generally reversible Supportive care including ventilation Antiepileptics Steroids

Cytopenia post CAR therapy Secondary to lymphodepletion HLH triggered by cytokine release syndrome GVHD of marrow (with allogeneic CARs)

Immunotherapy for myeloma - challenges Identify appropriate patient for a specific immunotherapy Identify predictive biomarkers for efficacy and toxicity Refine strategies for early recognition and management of expected and unexpected adverse events Education and training of clinicians and other health professionals in complications of immunotherapy Daycare/inpatient capacity

Immunotherapy for myeloma - recommendations Use Immunotherapy with caution ! Always think of potential immune related side effects Perform comprehensive investigations Serum cytokines Immune subsets analysis Biopsy and IHC of affected organ Appropriate imaging Involve relevant specialists early Low threshold for HDU/ICU care Report/publish all adverse events Share management strategies through regional/national disease groups