CAR T Cell Therapy

CAR T Cell Therapy Chimeric Antigen Receptor T cell therapy, or CAR T cell therapy, is an immunotherapy approach to treat cancer.

CAR T Cell Therapy Production The production of CAR T cell therapy involves a number of steps.1,2

T cells, a type of white blood The collected T cells are then sent CAR T cells are multiplied in the CAR T cells are intended to recognize cell, are collected from to a laboratory where they are lab and infused into the patient’s and kill the cancerous cells that have a patient or a donor’s blood. engineered to produce chimeric bloodstream. the targeted antigen on their surface antigen receptors (CARs) on their while also continuing to multiply surface. The engineered T cells are within the body. now called CAR T cells. T cell

Normal T cell CAR T cell

Tumor CARs

Approaches to CAR T Cell Therapy Development There are two approaches to the production of CAR T cell therapy. More research is needed to better understand the potential benefits and disadvantages of each approach.

Allogeneic Autologous Allogeneic CAR T cells are engineered using T cells from a single Autologous CAR T cells are engineered donor that are utilized in multiple patients. using a patient’s own T cells.

Healthy donor CAR T cells Patients Patient CAR T cells

Pfizer is Actively Pursuing Allogeneic CAR T Cell Therapy Through collaborations with Cellectis and Servier, Pfizer is actively investigating allogeneic CAR T cell therapies across several targets. Cellectis’s CAR T platform technology provides a proprietary, allogeneic approach to developing CAR T cell therapies that seeks to make genetically-engineered immunotherapy treatments that could potentially be used by multiple patients. The collaboration with Servier enables us to co-develop and potentially commercialize UCART19, an investigational allogeneic CAR T cell therapy.

1 Chimeric Antigen Receptor (CAR) T-Cell Therapy. Leukemia and Lymphoma Society. Available at https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy.

Accessed on February 10, 2016. 2 National Cancer Institute. CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers. Available at: http://www.cancer.gov/about-cancer/treatment/research/car-t-cells. Accessed on February 10, 2016.

May 2016 CCR2 Antagonist

PF‐04136309 CCR2 Inhibitor PF‐04136309 (PF-6309) is an investigational small-molecule antagonist of the human chemokine (C‐C motif) receptor 2 (CCR2) – a type of receptor that binds to cytokines (proteins that are involved in cell signaling).1,2

PF-6309 Mechanism of Action CCL2 is a chemoattractant that is released by tumor cells and binds to CCR2, which is expressed on the surface of monocytes (types of white blood cells) in the bone marrow. CLL2 is thought to play a role in the recruitment of monocytes from the bone marrow to the tumors, where these cells then become tumor associated macrophages (TAM). They in turn, have been observed to limit the effectiveness of anti-tumor immune responses, leading to tumor progression and chemoresistance.3 PF-6309 binds to CCR2 and has been observed to inhibit the binding of CCL2 to its receptor CCR2. The inhibition of CCR2 is thought to stop the recruitment of monocytes and reverse immune suppression within the tumor microenvironment.3,4,5

CCR2-CCL2 Pathway CCR2 Inhibition

tumor

PF-6309

CCR2 bind CCR2 MCP-1/ MCP-1/ CCL2 CCL2 monocyt e monocyt e monocyte

The Potential of CCR2 Inhibition Studies suggest that inhibition of CCR2 may have application in a variety of diseases, including cancer. Pre-clinical studies of PF‐6309 show anti-tumor activity in localized pancreatic cancer. PF-6309 has also been evaluated in an investigator initated Phase 1b dose escalation study in pancreatic cancer. More research is needed to fully understand the potential of CCR2 inhibition in cancer and identify potential immunotherapy combinations.

Clinical Study PF‐6309 is currently being studied in a Phase 1b/2 trial (dose escalation study followed by randomized Phase 2) for pancreatic cancer (NCT02732938).6

1. Zimmermann, W. et al. CCR1 and CCR2 Antagonists. Current Topics in Medicinal Chemistry 2014, 1539-1552. Available at: http://www.ingentaconnect.com/content/ben/ctmc/2014/00000014/00000013/art00005. Accessed April 13, 2016. 2. Miami Cancer Institute. Drug Dictionary. Available at: http://miamicancer.com/drug-dictionary/category/C/. Accessed April 13, 2016. 3. Nywening, T., et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non- randomised, phase 1b trial. The Lancet. 2016. http://dx.doi.org/10.1016/S1470-2045(16)00078-4. 4. Wang-Gillam, A., et al. Phase IB study of FOLFIRINOX plus PF-04136309 in patients with borderline resectable and locally advanced pancreatic adenocarcinoma (PC). Available at: http://meetinglibrary.asco.org/content/140478-158. Accessed April 13, 2016. 5. Deshmane, SL., et al. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. Journal of Interferon & Cytokine Research. 2009;29(6):313-326. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755091/. Accessed April 13, 2016. 6. Ph1b/2 Study of PF-04136309 in Combination With Gem/Nab-P in First-line Metastatic Pancreatic Patients (CCR2i). Available at: https://clinicaltrials.gov/ct2/show/NCT02732938?term=PF%E2%80%9004136309&rank=2. Accessed April 13, 2016.

PF-6309 is an investigational compound.

UTOMILUMAB (PF-05082566) Utomilumab is the proposed non-proprietary name for PF-05082566, an investigational immunotherapy and fully humanized monoclonalThe 4-1BB antibody(CD-137) protein (mAb) receptor administered is found intravenously on CD8+ and CD4+ that stimulatesT cells and natural signaling killer throughcells.1,2 Based 4-1BB on (CD-137), pre-clinical data, when utomilumab binds to 4-1BB,a itprotein stimulates expressed and increases in many the number immune of immunecells. cells.1 This may provide enhanced anti-tumor immune function.1 This is different from checkpoint inhibitors (i.e. PD-1, PD-L1), which act on another immune signaling pathway and are believed to work by inhibiting suppression of T cells.3 Mechanism of Action The 4-1BB (CD-137) protein receptor is found on CD8+ and CD4+ T cells and natural killer cells.1,2 Based on pre-clinical data, when CD8+ 1,2 utomilumabThe binds 4-1BB to 4-1BB, (CD-137) it stimulates protein and receptor increases is thefound number on CD8+ of immune and cells. CD4+Utomilumab1 This T cellsmay provideand natural enhanced killer anti-tumor cells. immune Activation 1 function.Based on This pre-clinical is different data,from checkpoint when utomilumab inhibitors (i.e. (PF-05082566) PD-1, PD-L1), which binds act to on 4-1BB, another it immune has been signaling observed pathway to andstimulateTumor are believed and increase the number of immuneto workcells. by1 This inhibiting may suppression provide enhanced of T cells.3 anti-tumor immune function.1 4-1BB Receptor NK

CD8+ Utomilumab T cell Activation CD4+ Tumor Proliferation

4-1BB Receptor NK

T cell CD4+ Proliferation

The Potential of Combination Approach Preclinical studies suggest that combining utomilumab (PF-05082566) with a checkpoint inhibitor, such as anti-PD-L1, or other immunotherapiesPreclinical studies may suggest be able that combiningto amplify utomilumab the immune with a checkpointresponse. inhibitor,4,5,6 Further such as understandinganti-PD-L1, or other the immunotherapies biology of how may be able to amplify the immune response.4,5,6 Further understanding the biology of how the immune system attacks tumors and ways by which tumors the immune system attacks tumors andevade ways the by immune which tumors system evademay lead the to immune a variety system of promising may leadcombinations to new investigational in the future. compounds.

Pfizer is exploringPfizer the is potentialexploring of the utomilumab potential of(PF-05082566) utomilumab in in a a clinical clinical developmentdevelopment program program to to determine: determine: Preclinical studiesCLINICAL suggest that combining utomilumab with a checkpoint inhibitor, such as anti-PD-L1, or other immunotherapies may be able CLINICALto amplify the immune • maximum response.4,5,6 tolerated Further• maximum understanding dose tolerated thedose biology of how the immune system attacks tumors and ways by which tumors STUDIES• anti-tumorevade the activity immune• efficacy andsystem safety may profilelead to a variety of promising combinations in the future. STUDIES • therapeutic potential in combination with other therapies • therapeutic potential in combination with other therapies

Pfizer is exploring the potential of utomilumab in a clinical development program to determine: CLINICALPhase 1• maximum tolerated dose Future studies PhaseSTUDIES 1Data from a Phase• efficacy 1 study that evaluated utomilumab in Future studiesPfizer will further explore utomilumab in order to better combination •with therapeutic rituximab potential in patients in combination with relapsed with or other therapies understand its efficacy and safety when used as both a single Data from a refractoryPhase 1 CD20+ study thatnon-Hodgkin’s evaluated lymphoma utomilumab (NHL) showed Pfizer will furtheragent andexplore in combination utomilumab with (PF-05082566) other anti-cancer in therapies, (PF-05082566)that utomilumabin combination demonstrated with rituximab anti-tumor in patients activity.7 order to betterincluding understand immunotherapies, its efficacy in several and safetytypes of when studies: withPhase relapsed 1 • Noor refractorydose-limiting CD20+ toxicities non-Hodgkin’s were observed usedFuture as both studies • a A singlePhase agent1 trial as and a single in combination agent in multiple with types lymphomaData from a Phase(NHL) and 1noshowed study patients that that discontinuedevaluated utomilumab utomilumab treatment in otherPfizer anti-cancerwill further of explore tumors therapies, utomilumab including in order immunotherapies, to better (PF-05082566)combination with due hadrituximab to treatment-relatedanti-tumor in patients activity. with adverse relapsed7 events. or inunderstand several types its efficacy of studies: and safety when used as both a single • A Phase 1 combination study with rituximab in refractory CD20+ non-Hodgkin’s lymphoma (NHL) showed agent and in combination with other anti-cancer therapies, • These results characterize the potential lymphoma patients •that No utomilumab dose-limiting demonstrated toxicities anti-tumor were observed activity.7 and •including A Phase immunotherapies, I study as a single in several agent types in multipleof studies: tumor efficacy for this investigational immunotherapy no patients discontinued treatment due to types and • in A combinationPhase 1 combination with rituximab study with in Merck lymphoma (U.S.) for • No dose-limiting when toxicities used in werecombination observed with a drug such • A Phase 1 trial as a single agent in multiple types treatment-related adverse events. 7 patients pembrolizumab (anti-PD-1) in solid tumors and no patients as rituximabdiscontinued that treatment has a different MOA. of tumors due to treatment-related adverse events. • A Phase 1 • combinationA Phase 1 combination study with study Merck with mogamulizumab(U.S.) for • These results characterize the potential activity • A Phase 1 combination study with rituximab in (anti-CCR4) in collaboration with KHK • Thesefor this results investigational characterize immunotherapy the potential when lymphomapembrolizumab patients (anti-PD-1) in solid tumors efficacy for this investigational immunotherapy • A Phase 1 combination study with Merck KGaA used in combination with a drug such as • • A PhasePhase 1 1combination combination study study with withMerck mogamulizumab (U.S.) for whenrituximab used in that combination has a different with a drug MOA. such7 and Pfizer’s PD-L1 avelumab as rituximab that has a different MOA.7 pembrolizumab(anti-CCR4) in (anti-PD-1) collaboration in solid with tumors KHK Studies evaluating 4-1BB or utomilumab have• • Abeen PhasePhase mentioned 1 1combination combination almost study study with 30 withmogamulizumab times Merck in severalKGaA and journals. (anti-CCR4)Pfizer’s PD-L1 in collaboration avelumab with KHK • A Phase 1 combination study with Merck KGaA For more information, please visit www.pfizercancertrials.com and Pfizer’s or www.clinicaltrials.gov PD-L1 avelumab or call toll-free 1-877-369-9753 (in the United States and Canada) or +1-646-277-4066 (outside of the United States and Canada). 1 Studies evaluating 4-1BB or utomilumab have been mentioned almost 30 times in several journals.

For more information, please visit www.pfizercancertrials.com or www.clinicaltrials.gov or call toll-free 1-877-369-9753 (in the United States and Canada) or +1-646-277-4066 (outside of the United States and Canada). 1 Fisher TS, Kamperschroer C, Oliphant T, et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity [published online ahead of print March 11, 2012]. Cancer Immunol Immunother. doi:10.1007/s00262-012-1237-1.

2 Westwood JA, Hunnam TC, Pegram HJ, et al. Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice. PLoS ONE. 2014; 9(5):1-10.

3 West, J., et al. Immune Checkpoint inhibitors, JAMA Oncol. 2015;1(1):115. doi:10.1001/jamaoncol.2015.0137. Available at http://oncology.jamanetwork.com/article.aspx?articleid=2174768.

4 Wei H, Zhao L, Li W, et al. Combinatorial PD-1 blockade and CD137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin. PLoS ONE. 2013; 8(12):1-11.

5 Curran MA, Kim M, Montalvo W, et al. Combination CTLA-4 blockage and 4-1BB activation enhances tumor rejection by increasing t-cell infiltration, proliferation, and cytokine production. PLoS ONE. 2011; 6(4):1-11.

6 Guo Z, Cheng D, Xia Z, et al. Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer.

7 Gopal, A., et al. A phase I study of PF-05082566 (anti-4-1BB) + rituximab in patients with CD20+ NHL. J Clin Oncol 33, 2015 (suppl; abstr 3004). Available at http://abstracts.asco.org/156/AbstView_156_147130.html.

2 OX40 AGONIST

PF-8600 (OX40 AGONIST) PF-04518600 (PF-8600) is an investigational immunotherapy monoclonal antibody (mAb) that targets the human OX40 protein (CD134), a receptor that is expressed on several types of T cells (types of immune cells).

Mechanism of Action OX40 protein is mostly expressed on T cells (CD4+ and CD8+) that have recently been exposed to antigens, for example tumor cells. When an OX40 agonist, such as PF-8600, binds to the OX40 protein receptor it triggers a co-stimulatory signal that is observed to be associated with increased production of T cells and inflammatory cytokines. This mechanism is thought to activate the dormant immune settings, which then may help fight cancer cells. Furthermore, in the tumor microenvironment (the cellular environment in which the tumor exists) OX40 agonist antibodies may suppress and/or reduce the regulatory T cells (Treg), which tend to inhibit effector T cell functions.

CD8+ PF-8600 Tumor

OX40 Receptor Co-stimulatory signal

CD8+ / CD4+ CD4+ Increased production of T cells and inflammatory cytokines

The Potential of Combination Approach Preclinical studies suggest that combining PF-8600 with a checkpoint inhibitor, such as anti PD-1/anti-PD-L1, or other immunotherapies may be able to amplify the immune response, and show additive activity in syngeneic tumor models. More research, however, is needed to fully understand the mechanism of action of these potential combination approaches.

Clinical Study

Phase 1 In 2015, Pfizer initiated a Phase 1 trial of PF-8600 in patients with select advanced solid tumors, such as hepatocellular carcinoma, melanoma, clear cell renal cell carcinoma, or squamous cell head and neck cancer. The estimated enrollment is 180 patients.