9/22/2016. Introduction / Goals. What is Cancer? Pharmacologic Strategies to Treat Cancer. Immune System Modulation

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1 Immunomodulatory Therapies in Cancer Treatment Bill O Hara, PharmD, BCPS, BCOP Advanced Practice Pharmacist, Oncology/BMT Thomas Jefferson University Hospital Introduction / Goals What is Cancer? How can we treat it? Role of the immune system in cancer. Modulation of the immune system to treat cancer What is Cancer? Pharmacologic Strategies to Treat Cancer Cancer is the result of one or more mutations in the DNA of a cell that leads to uncontrolled growth, self-sustained Immortality (avoid apoptosis) Promotion of angiogenesis Metastasis, or spread to other parts of the body *Avoid immune surveillance Directly cytotoxic agents Cell signaling blockade Immune system modulation Immune System Function and Immune Response Nonspecific First line of defense WBCs (natural killer cells, neutrophils) Activation of adaptive response Identify and destroy foreign or abnormal cells in the body Innate Immunity Macrophage Natural killer cell Complement protein Dendritic cell Basophil Eosinophil Neutrophil Mast cell Adaptive Immunity λδ T cell Natural killer T cell Granulocytes Specific Adapts specifically to diverse stimuli B-cell antibody production T-cell stimulation Memory functions Immune surveillance: Involves both innate and adaptive immune mechanisms Tumor-associated antigens can be identified by the immune system and destroyed Goal of immunotherapy for cancer: to educate and liberate underlying anticancer immune responses B cell Antibodies CD4+ T cell T cell CD8+ T cell Immune System Modulation Use immune system to eradicate cancer Cytokines: Aldesleukin, IL-2 Vaccines, adoptive immunotherapy: Sipuleucel-T *Immune Checkpoint Inhibitors: Ipilimumab, pembrolizumab, nivolumab Janeway CA Jr, et al. Immunobiology: the immune system in health and disease. Slide credit: clinicaloptions.com 1

2 History of Immunotherapy History of Immunotherapy When was the first documented use of immunotherapy to treat cancer? A (Red) B (Green) C (Yellow) D (Black) Coley Vaccine (Mixed Bacterial Vaccine), also known as Coley's Toxins Developed by a surgeon named William Coley in Sterile mixture of gram-positive Streptococcus pyogenes and gramnegative Serratia marcescens bacteria. Mimic an infection (producing chills and fever) and accompanying immune response, without incurring the risks of an actual infection. As head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. Cancer Immunoediting Key concepts in Immune Modulation Immunoediting Cancer Immunity Cycle Immunity, Vol. 21, , August, 2004, The Cancer Immunity Cycle Daniel S. Chen, Ira Mellman Immunity Volume 39, Issue 1, 2013,

3 Step 1: Release of Cancer Cell Antigens Cytotoxic chemotherapy Targeted therapy Target specific cells Less suppression of immune system Step 2: Cancer Antigen Presentation Sipuleucel-T (Provenge) Vaccines, adoptive immunotherapy: Sipuleucel-T Talimogene laherparepvec (Imlygic, T-VEC) 3

4 Step 3: Priming and Activation Key step in immune response Antigens that are determined to be foreign are presented to T cells for activation Aldesleukin (IL-2): T cell growth factor Ipilimumab: Immune checkpoint inhibitor IL-2 (Aldesleukin) Therapy IL-2 is a cytokine that functions as a T-cell growth factor Produced by activated T cells High-dose IL-2 produces durable responses in 6%-10% of patients with advanced melanoma a or RCC/mRCC b Capillary leak syndrome, requires inpatient stay with ICU availability a. Atkins MB, et al. J Clin Oncol. 1999;17: [18] ; b. McDermott DF, Atkins MB. Expert Opin Biol Ther. 2004;4: [19] ; c. Proleukin PI [17] Question: What are Immune Checkpoints? Immune Checkpoints A (Red). Receptors that amplify the immune response B (Green). Receptors that block the immune response C (Yellow). Receptors that present antigen to T cells D (Black). Receptors that cause cell activation? Immune checkpoints are able to turn off the immune response Often referred to as T cell exhaustion Limits extent and duration of immune response Protects immune system from attacking self-antigens Cancer cells can use these checkpoints to evade immune surveillance. Ipilimumab Immune checkpoint inhibitor Binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) Blockade of CTLA-4 augments T-cell activation and proliferation Can result in severe and fatal immune-mediated adverse reactions due to T-cell activation. REMS program 4

5 Summary of CTLA-4 Blockade Immune- Mediated Toxicities Toxicity related to ipilimumab appears to be dose related Common (> 20%) Rash, pruritus Fevers, chills, lethargy GI: Diarrhea/colitis Occasional (3% to 20%) Hepatitis/liver enzyme abnormalities Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency Vitiligo Rare (< 2%) Episcleritis/uveitis Pancreatitis Nephritis Neuropathies, Guillain-Barré, myasthenia gravis Lymphadenopathy (sarcoid) Thrombocytopenia Toxic epidermal necrolysis, Stevens- Johnson syndrome BiTe Weber JS, et al. J Clin Oncol. 2012;30: Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print]. Step 6: Recognition of Cancer Cells by T cells (CAR)-T Cell Mechanism Chimeric Antigen Receptor (CAR) T cells Patient s own T cells engineered to display receptor for specific cancer antigen Bi-specific T cell engager (BiTe) Anti-CD19/CD3 monoclonal antibody The BiTE antibody principle. Bi-specific T-cell engager (BiTe) Blinatumomab: Anti-CD19/CD3 monoclonal antibody B-cell ALL. 28 day CI, First week of cycle 1 as inpatient. Cytokine release syndrome, neurotoxicity, tumor lysis $100,000 per cycle (up to 5 cycles) Patrick A. Baeuerle, and Carsten Reinhardt Cancer Res 2009;69: by American Association for Cancer Research 5

6 Step 7: Killing of Cancer Cells Programmed Death (PD1) / Programmed Death-Ligand (PD-L1) Checkpoint that is read as self, blocks T cell action. Can be used by cancer cells to evade detection Blockade of PD-1 Signaling in Tumor Immunotherapy. Ribas A. N Engl J Med 2012;366: Summary of PD-1/PD-L1 Blockade Immune- Mediated Toxicities Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy. Occasional (5% to 20%) Fatigue Rash: maculopapular and pruritus Topical treatments Diarrhea/colitis Initiate steroids early, taper slowly Hepatitis/liver enzyme abnormalities Infusion reactions Endocrinopathies: thyroid, adrenal, hypophysitis Infrequent (< 5%) Pneumonitis Grade 3/4 toxicities uncommon Topalian SL, et al. N Engl J Med. 2012;366: Patnaik A, et al. ASCO Abstract Brahmer JR, et al. N Engl J Med. 2012;366: Herbst RS, et al. ASCO Abstract Ribas A. N Engl J Med 2012;366:

7 Selected clinical trials of immunotherapies Drugs Target Dual T-cell checkpoint blockade Ipilimumab + nivolumab CTLA-4 + PD-1 Ipilimumab + pembrolizumab CTLA-4 + PD-1 Tremelimumab + MEDI4736 CTLA-4 + PD-L1 Nivolumab + BMS PD-1 + LAG-3 T-cell blockade + costimulatory receptor agonists CP-870,893 + tremelimumab CTLA -4 + CD40 T-cell blockade + improving the function of innate immune cells Lirilumab + ipilimumab CTLA-4 + KIR Lirilumab + nivolumab PD-1 + KIR T-cell blockade + other immune system activators Denenicokin + ipilimumab CTLA-4 + IL21 Denenicokin + nivolumab PD-1 + IL21 INCB ipilimumab CTLA-4 + IDO Indoximod + sipuleucel-t IDO + vaccine Nivolumab + gp100, NY-ESO-1 PD-1 + vaccine Ipilimumab + sipuleucel-t CTLA-4 + vaccine Ipilimumab + TriMix-DC CTLA-4 + vaccine Ipilimumab + NY-ESO-1 vaccine CTLA-4 + vaccine Ipilimumab + adoptive cell transfer CTLA-4 + passive immunotherapy T-Vec BiTe Toxicities of checkpoint inhibitors include all of the following except? A. Autoimmune reactions B. Infusion reactions C. Economic toxicity D. T cell exhaustion Role of the Pharmacist Toxicity monitoring and treatment Each drug has algorithms available, holding drug +/- steroids Managing Costs: each therapy about $120,000 / year company programs (website), copay assistance New Combination therapies Markers of efficacy?: PD-1L expression, TILs, # of mutations Initial radiologic progression due to lymphocyte infiltration Questions? 7