CAR T Cell Therapy - pfe-pfizercom-d8-prod.s3.amazonaws.com › ... · Patient CAR T cells CAR T...
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Patient CAR T cells CAR T Cell Therapy Chimeric Antigen Receptor T cell therapy, or CAR T cell therapy, is an immunotherapy approach to treat cancer. 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 Allogeneic CAR T cells are engineered using T cells from a single donor that are utilized in multiple patients. Autologous Autologous CAR T cells are engineered using a patient’s own 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. CAR T Cell Therapy CAR T Cell Therapy Production The production of CAR T cell therapy involves a number of steps. 1,2 CAR T cells are intended to recognize and kill the cancerous cells that have the targeted antigen on their surface while also continuing to multiply within the body. CAR T cells are multiplied in the lab and infused into the patient’s bloodstream. The collected T cells are then sent to a laboratory where they are engineered to produce chimeric antigen receptors (CARs) on their surface. The engineered T cells are now called CAR T cells. T cells, a type of white blood cell, are collected from a patient or a donor’s blood. Tumor T cell Normal T cell CAR T cell CARs Healthy donor CAR T cells Patients May 2016
Transcript of CAR T Cell Therapy - pfe-pfizercom-d8-prod.s3.amazonaws.com › ... · Patient CAR T cells CAR T...
Patient CAR T cells
CAR T Cell TherapyChimeric Antigen Receptor T cell therapy, or CAR T cell therapy, is an immunotherapy approach to treat cancer.
Approaches to CAR T Cell Therapy DevelopmentThere 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.
AllogeneicAllogeneic CAR T cells are engineered using T cells from a single
donor that are utilized in multiple patients.
AutologousAutologous CAR T cells are engineered
using a patient’s own T cells.
Pfizer is Actively Pursuing Allogeneic CAR T Cell TherapyThrough 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.
CAR T Cell Therapy
CAR T Cell Therapy ProductionThe production of CAR T cell therapy involves a number of steps.1,2
CAR T cells are intended to recognize and kill the cancerous cells that have the targeted antigen on their surface
while also continuing to multiply within the body.
CAR T cells are multiplied in the lab and infused into the patient’s
bloodstream.
The collected T cells are then sent to a laboratory where they are
engineered to produce chimeric antigen receptors (CARs) on their
surface. The engineered T cells are now called CAR T cells.
T cells, a type of white blood cell, are collected from
a patient or a donor’s blood.
Tumor
T cell
Normal T cell CAR T cell
CARs
Healthy donor CAR T cells Patients
May 2016
PF‐04136309 CCR2 InhibitorPF‐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 ActionCCL2 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
The Potential of CCR2 InhibitionStudies 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 StudyPF‐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.
CCR2-CCL2 Pathway CCR2 Inhibitiontumor
MCP-1/CCL2
CCR2
monocyte
PF-6309
monocyte
tumor
MCP-1/CCL2
CCR2
monocyte
bind
CCR2 Antagonist
PF-6309 is an investigational compound.
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). May 2016
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UTOMILUMAB (PF-05082566)Utomilumab is the proposed non-proprietary name for PF-05082566, an investigational immunotherapy and fully
humanized monoclonal antibody (mAb) administered intravenously that stimulates signaling through 4-1BB (CD-137), a protein expressed in many immune cells.
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 utomilumab (PF-05082566) binds to 4-1BB, it has been observed to stimulate and
increase the number of immune cells.1 This may provide enhanced anti-tumor immune function.1
Preclinical studies suggest that combining utomilumab (PF-05082566) with a checkpoint inhibitor, such as anti-PD-L1, or other immunotherapies 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 evade the immune system may lead to new investigational compounds.
Mechanism of Action
The Potential of Combination Approach
Phase 1Data from a Phase 1 study that evaluated utomilumab in combination with rituximab in patients with relapsed or refractory CD20+ non-Hodgkin’s lymphoma (NHL) showed that utomilumab demonstrated anti-tumor activity.7
• No dose-limiting toxicities were observed and no patients discontinued treatment due to treatment-related adverse events.
• These results characterize the potential efficacy for this investigational immunotherapy when used in combination with a drug such as rituximab that has a different MOA.7
Future studiesPfizer will further explore utomilumab in order to better understand its efficacy and safety when used as both a single agent and in combination with other anti-cancer therapies, including immunotherapies, in several types of studies:
• A Phase 1 trial as a single agent in multiple types of tumors
• A Phase 1 combination study with rituximab in lymphoma patients
• A Phase 1 combination study with Merck (U.S.) for pembrolizumab (anti-PD-1) in solid tumors
• A Phase 1 combination study with mogamulizumab (anti-CCR4) in collaboration with KHK
• A Phase 1 combination study with Merck KGaA and Pfizer’s PD-L1 avelumab
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 utomilumab binds to 4-1BB, it stimulates and increases the number of immune 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
Preclinical studies suggest that combining utomilumab with a checkpoint inhibitor, such as anti-PD-L1, or other immunotherapies 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
evade the immune system may lead to a variety of promising combinations in the future.
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).
Studies evaluating 4-1BB or utomilumab have been mentioned almost 30 times in several journals.
Pfizer is exploring the potential of utomilumab in a clinical development program to determine: • maximum tolerated dose • efficacy• therapeutic potential in combination with other therapies
CLINICALSTUDIES
Proliferation
Utomilumab
T cell
ActivationTumor
CD8+
4-1BB Receptor
CD4+
NK
Phase 1Data from a Phase 1 study that evaluated utomilumab in combination with rituximab in patients with relapsed or refractory CD20+ non-Hodgkin’s lymphoma (NHL) showed that utomilumab demonstrated anti-tumor activity.7
• No dose-limiting toxicities were observed and no patients discontinued treatment due to treatment-related adverse events.
• These results characterize the potential efficacy for this investigational immunotherapy when used in combination with a drug such as rituximab that has a different MOA.7
Future studiesPfizer will further explore utomilumab in order to better understand its efficacy and safety when used as both a single agent and in combination with other anti-cancer therapies, including immunotherapies, in several types of studies:
• A Phase 1 trial as a single agent in multiple types of tumors
• A Phase 1 combination study with rituximab in lymphoma patients
• A Phase 1 combination study with Merck (U.S.) for pembrolizumab (anti-PD-1) in solid tumors
• A Phase 1 combination study with mogamulizumab (anti-CCR4) in collaboration with KHK
• A Phase 1 combination study with Merck KGaA and Pfizer’s PD-L1 avelumab
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 utomilumab binds to 4-1BB, it stimulates and increases the number of immune 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
Preclinical studies suggest that combining utomilumab with a checkpoint inhibitor, such as anti-PD-L1, or other immunotherapies 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
evade the immune system may lead to a variety of promising combinations in the future.
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).
Studies evaluating 4-1BB or utomilumab have been mentioned almost 30 times in several journals.
Pfizer is exploring the potential of utomilumab in a clinical development program to determine: • maximum tolerated dose • efficacy• therapeutic potential in combination with other therapies
CLINICALSTUDIES
Proliferation
Utomilumab
T cell
ActivationTumor
CD8+
4-1BB Receptor
CD4+
NK
4-1BB AGONIST
Pfizer is exploring the potential of utomilumab (PF-05082566) in a clinical development program to determine: • maximum tolerated dose • anti-tumor activity and safety profile• therapeutic potential in combination with other therapies
CLINICAL STUDIES
Future studiesPfizer will further explore utomilumab (PF-05082566) in order to better understand its efficacy and safety when used as both a single agent and in combination with other anti-cancer therapies, including immunotherapies, in several types of studies:• A Phase I study as a single agent in multiple tumor
types and in combination with rituximab in lymphoma patients
• A Phase 1 combination study with Merck (U.S.) for pembrolizumab (anti-PD-1) in solid tumors
• A Phase 1 combination study with mogamulizumab (anti-CCR4) in collaboration with KHK
• A Phase 1 combination study with Merck KGaA and Pfizer’s PD-L1 avelumab
Phase 1Data from a Phase 1 study that evaluated utomilumab (PF-05082566) in combination with rituximab in patients with relapsed or refractory CD20+ non-Hodgkin’s lymphoma (NHL) showed that utomilumab (PF-05082566) had anti-tumor activity.7
• No dose-limiting toxicities were observed and no patients discontinued treatment due to treatment-related adverse events.
• These results characterize the potential activity for this investigational immunotherapy when used in combination with a drug such as rituximab that has a different MOA.7
2
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.
Increased productionof T cells and inflammatory cytokines
PF-8600
CD8+ /CD4+
TumorCD8+
OX40 Receptor
CD4+
Co-stimulatory signal
The Potential of Combination Approach
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.
Phase 1In 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.
Clinical Study
OX40 AGONIST
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.
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).
