Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

  • ID: 4196736
  • Report
  • 218 Pages
  • Insight Pharma Reports
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FEATURED COMPANIES

  • Aduro Biotech
  • Bavarian Nordic
  • Celldex
  • Genelux
  • Kite Pharma
  • Nektar Therapeutics
  • MORE

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.”

Moreover, treatment of advanced melanoma (the cancer for which the largest amount of data on immunotherapy has been amassed) with checkpoint inhibitors has in some cases produced spectacular results. For example, data released at the May 2016 ASCO Annual Meeting indicate that 40% of metastatic melanoma patients who received pembrolizumab (Merck’s Keytruda) in a large clinical trial are still alive three years later. is represents a substantial improvement over just a few years ago, when the average survival time for patients with advanced melanoma was measured in months. 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
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FEATURED COMPANIES

  • Aduro Biotech
  • Bavarian Nordic
  • Celldex
  • Genelux
  • Kite Pharma
  • Nektar Therapeutics
  • MORE

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-15Ra (hetIL-15)
  • Altor’s ALT-803
  • Conclusions: Cytokine-based immunotherapies for cancer

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 PI3K? 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

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

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

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

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

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

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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FEATURED COMPANIES

  • Aduro Biotech
  • Bavarian Nordic
  • Celldex
  • Genelux
  • Kite Pharma
  • Nektar Therapeutics
  • MORE

What you will Learn:

  • Why is immuno-oncology important, in terms of advancing cancer treatment beyond the traditional modalities of chemotherapy, radiation therapy, and surgery? What is immuno-oncology 2.0, and how might it advance the field of cancer immunotherapy?
  • What are the major classes of current and emerging immuno-oncology therapeutics?
  • How do these agents work?
  • Which immuno-oncology drugs have been approved? Which late-stage agents are likely to reach the market in the next 5 years? How might these newer agents benefit patients?
  • How are researchers, physicians, and companies attempting to achieve improved results with immuno-oncology treatments, in terms of increasing the numbers of patients who benefit from these treatments, achieving improved patient survival, and treating previously untreatable and incurable types of cancer?
  • Why has there been such a high rate of failure in the field of therapeutic anticancer vaccines? How are researchers and companies attempting to use immuno-oncology 2.0 strategies to reduce the numbers of failures, and thus to benefit patients?
  • Why is neoantigen science important in immuno-oncology, especially in development of novel vaccines and cellular immunotherapies? Which academic research groups, and established and emerging companies, are developing neoantigen-based therapies?
  • What are the cellular immunotherapy products that are emerging in 2017? What are the issues in manufacturing cellular immunotherapy products, and in administering them to patients safely? Why has it been difficult to commercialize tumor infiltration lymphocyte (TIL) therapies, despite their success in treating metastatic melanoma?
  • What is the expected market size for cancer immunotherapy in the 2017-2024 period? How might that market size be affected by the entry of new immuno-oncology 2.0 agents, and of cellular immunotherapy products?
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  • Aduro Biotech
  • Amgen
  • Argos Therapeutics
  • Bavarian Nordic
  • Bellicum Pharmaceuticals
  • bluebird bio
  • Celldex
  • Cellectis
  • Dendreon
  • Genelux
  • Genentech
  • Juno Therapeutics
  • Kite Pharma
  • MacroGenics
  • MedImmune
  • Nektar Therapeutics
  • Novartis
  • Regeneron
  • Roche
  • Sydys Corporation
  • TapImmune
  • Valeant
  • Xencor
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