CANCER IMMUNOTHERAPY - Building on Initial Successes to Improve Clinical Outcomes

INTRODUCTION

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 how 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.

As discussed in our 2014 report and still true in early 2017, the most successful class of immunotherapeutics has been the checkpoint inhibitors (which are discussed in this report). Checkpoint inhibitors and other immuno-oncology agents represent a significant advance in cancer treatment beyond the traditional modalities of chemotherapy, radiation therapy, and surgery. 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 3 years later. This represents a substantial improvement over just a few years ago, when the average survival time for patients with advanced melanoma was measured in months.

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. Thus, researchers have been developing biomarkers that distinguish inflamed (ie, 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.

APPROVALS OF CHECKPOINT INHIBITORS

Researchers are continuing to conduct clinical trials designed to gain approval for new checkpoint inhibitors and for new indications for already approved agents. Notable recent developments include the 2016 approval of atezolizumab (Roche/Genentech’s Tecentriq), the first PD-L1 (programmed death-ligand 1) inhibitor to be approved. On May 18, 2016, atezolizumab was approved by the FDA for treatment of advanced or metastatic urothelial carcinoma that has worsened during or following platinum-containing chemotherapy or within 12 months of receiving platinum-containing chemotherapy, either before or after surgical treatment. Later, on October 18, 2016, the FDA ap- proved atezolizumab for use in patients with metastatic NSCLC (regardless of PDL1 expression) who have progressed during or after treatment with a platinum-based chemotherapy or appropriate targeted therapy.

Also in October 2016, the FDA approved the PD-1 (programmed cell death protein 1) inhibitor pembrolizumab as a monotherapy for first-line treatment of patients with advanced NSCLC whose tumors expressed PD-L1 at ≥ 50%. This was after this agent met its primary endpoint of progression-free survival in patients with previously untreated advanced NSCLC whose tumors expressed PD-L1 at ≥ 50%. In contrast, monotherapy with the competing PD-1 inhibitor nivolumab (Bristol-Myers Squibb’s Opdivo) did not meet its primary endpoint of progression-free survival in patients with previously untreated advanced NSCLC whose tumors expressed PD-L1 at ≥ 5%. This result is affecting the competition between BMS’ nivolumab and Merck’s pembrolizumab.

APPROVED & CLINICAL-STAGE IMMUNOTHERAPY BIOLOGICS OTHER THAN CHECKPOINT INHIBITORS

In addition to serving as an introduction to the report and discussing the early history of cancer immunotherapy, the beginning of the report focuses on cytokines as cancer immunotherapeutics. Interleukin-2, interferon-alpha-2a, and interferon alpha-2b have long been approved for treatment of various cancers. To this day, despite the introduction of newer immunotherapies, such as checkpoint inhibitors, high-dose recombinant IL-2 (Novartis/Prometheus Laboratories’ Proleukin) is the only drug so far that has produced durable, long-term responses in patients with metastatic melanoma or metastatic renal cell carcinoma. According to Patrick Ott, MD, PhD, of the Dana-Farber Cancer Institute in Boston, MA, “High-dose IL-2 has a track record of patients who have been disease-free for 20 years, and we just don’t know that yet with the new drugs [such as checkpoint inhibitors].” In the case of advanced melanoma, high-dose intravenous bolus IL-2 induces objective clinical responses in 15% to 20% of patients and durable complete responses in 5% to 7% of these patients. For metastatic RCC (mRCC), high-dose intravenous bolus IL-2 gives an objective clinical response rate of approximately 25% and a 7% durable complete response rate.

In addition to discussing approved and clinical-stage checkpoint inhibitors and their mechanisms of action, the report includes discussions of clinical-stage checkpoint inhibitor modulators, such as LAG-3 (lymphocyte-activation gene 3) inhibitors, TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) inhibitors, small-molecule IDO (indoleamine 2,3-dioxygenase) pathway inhibitors, and a small-molecule PI3K (phosphoinositide 3-kinase gamma) inhibitor. These agents are in Phase 1 or Phase 2 development. In general, they work to overcome immunosuppression and/or T-cell exhaustion, and thus may overcome blocks to T-cell activation by checkpoint inhibitors.

IMMUNE AGONISTS

The report focuses on immune agonists. Immune agonist therapeutics – most of which are mAbs – target specific cell surface proteins on T-cells, resulting in stimulation of T- cell activity. This mechanism contrasts with that of checkpoint inhibitors, which are designed to overcome blockages to T-cell activity mediated by immune checkpoints. Companies are developing immune agonist immunotherapeutics principally for use in combination with checkpoint inhibitors (ie, as immuno-oncology 2.0 agents). All the agents discussed in this report are in early stage clinical trials.

BISPECIFIC ANTIBODIES

The report discusses bispecific antibody (bsAb) cancer immunotherapeutics, which are a type of mAb. bsAbs are designed with two different variable domains that enable the Ab to bind simultaneously to two different types of targets. bsAbs used in cancer immunotherapy usually bind one target on a tumor cell and another target on a cytotoxic immune system cell, bringing the two types of cells into proximity. This allows the immune system to act against the tumor cell.

ANTICANCER VACCINES

This section of the report focuses on therapeutic anticancer vaccines and oncolytic viruses. Efforts to develop therapeutic cancer vaccines began in the 1990s. However, the cancer vaccine field has been characterized by a long series of clinical failures, beginning in the 1990s and continuing to the present day. Researchers have been working to overcome these difficulties by using improved research methodologies and by employing advances in our understanding of immuno-oncology. In the current era, researchers have used their greater understanding of dendritic cell biology to attempt to improve the design of peptide and protein vaccines. Another important factor that has contributed to the failure of cancer vaccines is immune suppression in the tumor environment. Some researchers hypothesize that one way to overcome this immunosuppression is to administer vaccines in combination with checkpoint inhibitors.

In 2015, the FDA approved talimogene laherparepvec (Amgen’s Imlygic, also known as T-Vec), an oncolytic herpes simplex virus that expresses granulocyte macrophage colony-stimulating factor (GM-CSF). It is approved for the treatment of melanoma lesions in the skin and lymph nodes. This oncolytic virus is injected into a single tumor, where it lyses tumor cells. It was postulated that upon lysis of tumor cells in the treated lesion, systemic immune responses are induced. There was evidence for induction of immune responses in distant tumor sites in a published Phase 1 study, and there was a trend toward improved overall survival in early results of a Phase 3 study presented at the 2013 ASCO Annual Meeting. However, as determined by completed results of the same Phase 3 study, the agent was not subsequently shown to improve overall survival or influence distant metastases.

Imuno-oncology 2.0 strategies now feature prominently in therapeutic cancer vaccine and oncolytic virus therapeutic development. This is particularly true with neoantigen vaccines, which are designed to induce neoantigen-specific TILs within patients’ tumors. The strategy is to use the vaccine to induce the TILs, rendering checkpoint inhibitors effective in inducing tumor regression. Based on this strategy, Neon’s NEO-PV-01 vaccine is being combined with poly-ICLC adjuvant and Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor nivolumab in collaborative clinical studies in advanced melanoma, smoking-associated NSCLC, and bladder cancer.

The immuno-oncology 2.0 strategy has become a general theme of cancer vaccine research and development beyond neonantigen vaccines – use cancer vaccines to render tumors inflamed, and use checkpoint inhibitors to induce regression of the inflamed tumors. Thus, there are several examples of trials of cancer vaccine/checkpoint inhibitor combinations discussed in this section of the report. In some cases, cancer vaccines are being tested in combination with checkpoint inhibitors in Phase 1 or Phase 2 clinical trials, rather than the “traditional” approach of first getting a vaccine approved and then conducting trials of the vaccine in combination with other agents. It is possible that testing a vaccine in combination with a checkpoint inhibitor in early stage clinical trials may reduce the number of failed cancer vaccines. However, whether this is true remains to be seen.

This report focuses on the use of adoptive T-cell immunotherapies for cancer. In this class of therapies, autologous or syngeneic activated T-cells (which may or may not be genetically modified) are infused into patients to attack their cancers. Adoptive immunotherapy is also known as adoptive cell transfer (ACT).

IMMUNOTHERAPY WITH TIL CELLS

ACT was pioneered by Dr. Steven A. Rosenberg of the National Cancer Institute (NCI). The major focus of the Rosenberg group has been TIL therapy, which involves isolation of TILs (which are tumor-infiltrating T-cells) from a patient’s tumor, followed by ex vivo expansion of these cells with IL-2. The TILs and high-dose IL-2 are then infused intravenously into the patient. The infused T- cells traffic to tumors and can mediate their destruction. Clinical study of TIL therapy has continued to the present day. Moreover, attempts to overcome some of the limitations of TIL therapy have resulted in the development of other newer forms of ACT based on various types of genetically engineered T-cells.

Kite Pharma, which expects to complete its submission for marketing of KTE-C19 (axicabtagene ciloleucel) in the first quarter of 2017, opened a 43,500-sq-ft state-of-the-art T-cell therapy manufacturing facility near Los Angeles International Airport in June 2016. This manufacturing plant is designed to support production of engineered CAR and TCR cellular immunotherapies. The facility has been designed to produce CAR and TCR product candidates for clinical trials, as well as to produce KTE-C19 (axicabtagene ciloleucel) for its anticipated launch and commercialization in 2017.

ADOPTIVE IMMUNOTHERAPY VIA AUTOLOGOUS RECOMBINANT TCR TECHNOLOGY

Other researchers and companies are developing autologous T-cell therapies based on recombinant TCRs. Adaptimmune is the leader in this field. Adaptimmune has designed autologous T-cells engineered with an increased affinity recombinant TCR that targets the cancer testis antigen NY-ESO-1. Adaptimmune is developing its NY-ESO-1 recombinant TCR therapeutic candidate in partnership with GSK as the result of a 2014 strategic collaboration and licensing agreement between the two companies.

Phase 1/2 clinical trials for the anti-MAGE-A10 TCR therapy in advanced NSCLC were initiated in late 2015. In 2016, the company added a Phase 1 study of the MAGE-A10 TCR therapy in urothelial cancer, melanoma, and head and neck cancers. In both cases, patients selected for the trials must test positive for HLA-A*0201 and/or HLA-A*0206 protein (in accordance with the MHC restriction of the recombinant TCR), and their tumors must test positive for MAGE-A10 expression.

Another Adaptimmune recombinant TCR therapeutic is designed to target alpha fetoprotein (AFP), which is associated with hepatocellular carcinoma. The FDA accepted the company’s investigational new drug (IND) application for this therapy in April 2016. Adaptimmune plans to evaluate this candidate in a Phase 1 study, and site selection activities are underway.

GENERAL CONCLUSIONS ON THE PROGRESS OF CELLULAR IMMUNOTHERAPY

There are two CAR T-cell therapies that are expected to reach the preregistration stage with the FDA in early 2017 – Novartis’ CTL019 and Kite’s KTE-C19/axicabtagene ciloleucel. Both of these target CD19 and are indicated for treatment of B-cell leukemias and/or lymphomas. The approval and marketing of one or both therapies will represent a milestone in cancer immunotherapy and will enable cellular immunotherapy to take its place beside checkpoint inhibitor therapies as an important (and marketed) modality of immunotherapy for cancer. Both therapies were approved by the FDA later in 2017, after the publication of our report.

Another focus of cellular immunotherapy is the development of engineered improvements in CAR T cell therapy. Cellectis is using gene-editing technology to design “off-the-shelf” allogenic CAR T-cell therapies that do not require the patient-specific manufacturing protocols needed for conventional autologous CAR T-cell therapies. Like biologics, the production of Cellectis’ CAR T-cell therapies can be industrialized and standardized with consistent pharmaceutical release criteria. Meanwhile, Bellicum is developing CAR T-cell therapies that incorporate inducible activation switches that allow for continuing antitumor surveillance or serve as safety switches to eliminate cells in the event of toxicity. Notably, Bellicum postulates that its proprietary cellular controls may enable successful treatment of solid tumors by CAR T-cell therapeutics.

OUTLOOK FOR CANCER IMMUNOTHERAPY

This report includes the results of a survey on immuno-oncology that Insight Pharma Reports conducted in conjunction with this report. It also includes the general conclusions of the report and a discussion of the outlook for cancer immunotherapy. Regular use of immunotherapy for treatment of cancer, which has been an elusive dream for more than 100 years, has very recently come within the grasp of researchers, physicians, and patients. As of the early to mid 2010s, cancer immunotherapy has become a “hot” area, with intense competition between biotechnology and pharmaceutical companies to be the first to market the newest, most effective therapies.

Moreover, building on the initial successes of researchers and companies in development and marketing of cancer immunotherapies, researchers, companies, and oncologists have been moving toward immuno-oncology 2.0 strategies that can achieve improved outcomes for more patients. Thus, as mentioned earlier, ASCO’s 12th Annual Report on Progress Against Cancer (2017) named Immunotherapy 2.0 as its Advance of the Year.

In August 2015, Forbes estimated that approximately 20% to 25% of Bristol-Myers Squibb’s valuation was based on the expected growth of its cancer drugs, primarily ipilimumab and nivolumab. Forbes expected the sales of these two checkpoint inhibitors to grow from $1.3 billion in 2014 to almost $7.5 billion by 2022. The same article projected a market for immuno-oncology drugs (principally checkpoint inhibitors) over the same period that could reach $35 billion.

In conclusion, immuno-oncology has begun to fulfill its promise as a game-changing approach to treating cancer. It is likely to constitute a new mode of cancer treatment, alongside surgery, chemotherapy (including treatment with cytotoxic and/or targeted drugs), and radiation therapy. Immunotherapies may eventually be used in as many as 60% of cases of advanced cancer. Immuno-oncology 2.0 approaches – as well as the successful development and commercialization of TIL-based treatments and recombinant T-cell therapies – may enable improved cancer treatments that can produce greater numbers of remissions, and even cures, for cancers that have been uniformly fatal until very recently. Thus, immuno-oncology continues to be an important and rapidly emerging field that is deserving of the attention it has been receiving in recent years.

This article is based on the following market research report published by Insight Pharma Reports: Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes by Allan Haberman, PhD. For more information, visit http://www.insightpharmareports.com/Cancer-Immunotherapy-2017-Report/.

Dr. Allan B. Haberman is Principal of Haberman Associates and a Founder and Principal of the Biopharmaceutical Consortium. Dr. Haberman’s consulting activities include work in new product development and technology strategy, opportunity assessment, assessment of drug pipelines, and due diligence on established and emerging biotechnology companies. He is also the author of numerous books, reports, and articles on the pharmaceutical and biotechnology industry, R&D strategy, therapeutic area and pipeline strategy, and technology assessment. Dr. Haberman also speaks at national and international conferences on the pharmaceutical and biotechnology industry and on drug discovery and development. Prior to forming Haberman Associates, Dr. Haberman was the Associate Director of the Biotechnology Engineering Center at Tufts University. He earned his PhD in Biochemistry and Molecular Biology from Harvard University.