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Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

This new report builds on our 2014 Insight Pharma Report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies. In that report, we focused on the major classes of cancer immunotherapy drugs that were then emerging from academic and corporate research: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies. This new report includes an updated discussion of approved and clinical stage agents in immuno-oncology, including recently-approved agents. It also addresses the means by which researchers and companies are attempting to build on prior achievements in immuno-oncology to improve outcomes for more patients. Some researchers and companies refer to this approach as “immuno-oncology 2.0.” The American Society of Clinical Oncology (ASCO), in its 12th Annual Report on Progress Against Cancer (2017), named “Immunotherapy 2.0” as its “Advance of the Year.”

 
Nevertheless, metastatic melanoma remains incurable. Furthermore, in many studies in advanced melanoma and other cancers, only a minority of patients have benefited from immunotherapy treatments. Researchers and companies are therefore looking for ways to build on the initial successes of the immuno-oncology field to improve outcomes for more patients, hence the need for an “immuno-oncology 2.0.”  Agents that are intended to improve the results of treatment with agents like checkpoint inhibitors may also be referred to as “second-wave” immuno-oncology agents.

As discussed in this report, researchers have found that checkpoint inhibitors produce tumor responses by reactivating TILs (tumor infiltrating lymphocytes)—especially CD8+ cytotoxic T cells. This key observation is perhaps the most important factor driving development of second-wave immuno-oncology strategies. As a result, researchers have been developing biomarkers that distinguish inflamed (i.e., TIL-containing) tumors—which are susceptible to checkpoint inhibitor therapy—from “cold” tumors, which are not. They have also been working to develop means to render “cold” tumors inflamed, via treatment with various conventional therapies and/or development of novel agents. These studies are the major theme of “second-wave” immuno-oncology, or “immuno-oncology 2.0.”
 
Highlights of this Report Include:
Approvals of checkpoint inhibitors
Biomarkers for checkpoint inhibitor treatments
Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors
Immunotherapy with TIL cells
Commercialization of TIL therapy
Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs)
Manufacturing issues with CAR T-cell therapies
General conclusions on the progress of cellular immunotherapy
Outlook for cancer immunotherapy


EXECUTIVE SUMMARY
Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes 
Approvals of checkpoint inhibitors 
Biomarkers for checkpoint inhibitor treatments 
Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors 
Immunotherapy with TIL cells 
Commercialization of TIL therapy 
Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) 
Manufacturing issues with CAR T-cell therapies 
Adoptive immunotherapy via autologous recombinant TCR technology 
General conclusions on the progress of cellular immunotherapy 
Outlook for cancer immunotherapy 
About Cambridge Healthtech Institute 
CHAPTER 1:
Introduction 
The early history of cancer immunotherapy – Coley’s toxins 
Cytokines as immunomodulatory drugs
Interleukin-2 
Alpha-interferons 
Interleukin-12 
Interleukin-12 as a bridge between innate and adaptive immunity 
Investigation of interleukin-12 as an anticancer therapeutic 
Interleukin-10 
Interleukin-15 
Admune/Novartis’ heterodimeric IL-15:IL-15Rα (hetIL-15) 
Altor’s ALT-803 
Conclusions: Cytokine-based immunotherapies for cancer 
CHAPTER 2:
What are immune checkpoints? 
CTLA-4 blocking agents 
Ipilimumab 
Tremelimumab 
PD-1 blocking agents 
Nivolumab 
Combination therapy of nivolumab plus ipilimumab in melanoma 
Pembrolizumab 
Pembrolizumab as a first-line treatment for advanced NSCLC 
Pembrolizumab in colorectal carcinoma with mismatch-repair deficiency 
Studies of pembrolizumab in combination immunotherapies 
PDR001 
PD-L1 blocking agents 
Atezolizumab 
Atezolizumab in treatment of urothelial carcinoma 
Atezolizumab for the treatment of NSCLC 
Atezolizumab in treatment of other solid tumors 
Other anti-PD-L1 mAb agents 
Durvalumab 
Avelumab 
Anti-LAG-3 agents 
anti-TIM-3 
NewLink Genetics’ small-molecule IDO pathway inhibitors and checkpoint inhibition 
Infinity’s PI3Kγ inhibitor IPI-549 for modulation of immune suppression in tumors 
Biomarkers for checkpoint inhibitor treatments 
Target biomarkers 
Genetic biomarkers 
Immunological biomarkers 
Use of biomarker tests in treatment with checkpoint inhibitors 
Checkpoint inhibitors plus radiation therapy 
Checkpoint inhibitors plus targeted therapies 
Checkpoint inhibitors with cytotoxic chemotherapies 
Discussion 
CHAPTER 3:
Immune Agonists 
Celldex Therapeutics’ Varlilumab (CDX-1127) 
OX40 agonists 
MedImmune/AZ’s OX40 agonist program 
Roche/Genentech’s OX40 agonist program 
Nektar Therapeutics/BMS’s NKTR-214, a CD122 agonist 
Glucocorticoid-induced TNFR-related (GITR) protein agonist (Leap Therapeutics’ TRX518) 
Conclusions 
CHAPTER 4:
Bispecific antibodies 
Marketed bispecific antibody agents 
Catumaxomab 
Blinatumomab 
Bispecific antibodies as an alternative to CAR-T cells 
Xencor’s cross-linking monoclonal antibody (XmAb) bispecific platform technology 
Regeneron’s native human immunoglobulin-format bsAb, REGN1979 
Roche/Genentech’s full-length bsAbs: Generated using CrossmAb technology 
MacroGenics’ MGD007: Generated using dual-affinity re-targeting (DART) technology 
Conclusions 
CHAPTER 5:
Therapeutic Anticancer Vaccines and Oncolytic viruses 
Introduction
Cancer vaccines—a field rife with clinical failures 
Why has the cancer vaccine field been so prone to clinical failure? 
Marketed therapeutic cancer vaccines and oncolytic virus therapies 
Dendreon/Valeant’s sipuleucel-T 
Amgen’s talimogene laherparepvec (T-Vec)/Imlygic 
Therapeutic cancer vaccines and oncolytic virus therapies in clinical development 
Celldex’s CDX-1401 
Bavarian Nordic’s PROSTVAC-VF 
Argos Therapeutics’ AGS-003 
Sydys Corporation’s CVac 
Aduro Biotech’s CRS-207 
TapImmune’s TPIV110 HER2/neu and TPIV200 folate receptor alpha multi-epitope vaccines 
Genelux’s GL-ONC1 oncolytic virus 
Conclusions 
CHAPTER 6:
Adoptive Immunotherapy for Cancer 
Introduction 
Adoptive immunotherapy with tumor infiltrating lymphocytes 
A specific immunodominant mutation in a melanoma patient who had a durable complete remission due to TIL therapy 
Adoptive immunotherapy based on mutation-specific CD4+ T cells in an epithelial cancer 
Successful targeting of KRAS G12D via adoptive immunotherapy in a case of metastatic colorectal cancer 
Dr. Rosenberg’s recent studies on neoantigen-reactive TILs for use in adoptive cellular immunotherapy 
Commercializing TIL therapy 
Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) 
Leading clinical programs in CAR T-cell based immunotherapy 
Kite Pharma’s KTE-C19 (axicabtagene ciloleucel) 
Novartis’ CTL019 
Juno’s JCAR015 and other Juno anti-CD19 CARs 
Other CAR T-cell therapies that target hematologic malignancies 
bluebird bio’s bb2121 for multiple myeloma 
CAR T-cell therapies that target solid tumors 
Novartis/University of Pennsylvania’s CARTmeso 
EGFRvIII CAR T-cell therapies 
Companies developing engineered improvements in CAR T-cell therapy 
Bellicum Pharmaceuticals’ technologies for modulation of CAR T-cell therapies 
Cellectis’ technologies for design and manufacture of “off-the shelf” CAR T-cell therapies 
Manufacturing issues with CAR T-cell therapies 
Can bispecific antibodies be competitive with CAR T-cell therapies? 
Adptimmune recombinant TCR clinical candidates 
Kite Pharma recombinant TCR program 
Juno Therapeutics’ recombinant TCR program 
Recombinant TCR studies at the NCI 
Conclusions 
Market size estimates for the T-cell therapy market 
CHAPTER 7:
General Conclusions 
Major theme of this report: Immuno-oncology 2.0 or “second-wave” immuno-oncology 
Approvals of checkpoint inhibitors 
Biomarkers for checkpoint inhibitor treatments 
Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors 
Immunotherapy with TIL cells 
Commercialization of TIL therapy 
Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) 
Manufacturing issues with CAR T-cell therapies 
Adoptive immunotherapy via autologous recombinant TCR technology 
General conclusions on the progress of cellular immunotherapy 
Insight Pharma Reports survey on cancer immunotherapy 
Outlook for cancer immunotherapy 
References 
Tables and Figures
Tables
Table 1.1: Title
Table 2.2: Biomarkers for Use in Clinical Studies of Checkpoint Inhibitors
Table 3.1: Select Immune Agonists for Cancer Immunotherapy
Table 4-1: Select Bispecific Antibody Agents for Cancer Immunotherapy
Table 5-2: Select Cancer Vaccines Approved and in Clinical Development
Table 6-1: Select cellular immunotherapies in commercial development
Figures
Figure 2.1: T Cell Costimulation by CD28 and Checkpoint Control by CTLA-4
Figure 4.1: Bispecific antibodies in immuno-oncology
Figure 6.1: Bispecific antibodies in immuno-oncology

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