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.”
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 Chapter 2 of 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 three 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.
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.”
Approvals of checkpoint inhibitors
As discussed in Chapter 2, 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 approved atezolizumab for use in patients with metastatic NSCLC (regardless of PD-L1 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.
In Merck’s KEYNOTE-024 trial, the patient population that was treated with either pembrolizumab or chemotherapy consisted of individuals with previously untreated advanced NSCLC whose tumors expressed PD-L1 at ≥50%. In contrast, BMS’ CheckMate 026 trial of nivolumab as a monotherapy evaluated the drug in patients with previously untreated advanced NSCLC whose tumors expressed PD-L1 at only ≥5%. This difference in trial design may explain the divergent results of the two trials, rather than a potential superior efficacy of pembrolizumab over nivolumab. Nevertheless, the results of the KEYNOTE-024 trial advance the prospects of Merck’s pembrolizumab for first-line treatment of advanced NSCLC with high levels of PD-L1 expression, while BMS must conduct an evaluation of its study and decide what to do next.
In addition to the discussions of approved checkpoint inhibitors, Chapter 2 also includes discussions of clinical stage agents in this class. These include Novartis’ PD-1 inhibitor PDR001, AstraZeneca’s PD-L1 inhibitor durvalumab, and Merck-Serono/Pfizer’s PD-L1 inhibitor avelumab. Notably, avelumab has been under evaluation in a pivotal Phase 2 trial in Merkel cell carcinoma, with favorable results reported in the 2016 ASCO annual meeting. Merck-Serono and Pfizer plan to submit the drug to regulatory authorities based on these results.
Biomarkers for checkpoint inhibitor treatments
The later sections of Chapter 2 discuss the role of biomarkers in checkpoint inhibitor treatments, especially in the context of “immuno-oncology 2.0.” “Immuno-oncology 2.0” may involve development of novel agents, such as those discussed in this and other chapters of the report. It may also involve combining different immunotherapies, combining immunotherapies with older types of treatments and/or with new experimental treatments, or other novel approaches. The development and use of biomarkers will be key to the progress of “immuno-oncology 2.0.” Biomarkers will help researchers and physicians predict responses to immunotherapy treatments. Such tests may not only spare patients the costs and adverse effects of treatments that may not help them, but may also help researchers to design optimal, “personalized” treatments.
Several classes of biomarkers are in use and/or development for cancer immunotherapy, and especially for use in combination with checkpoint inhibitors. A target biomarker is a biomarker that reflects the presence of a specific molecular drug target. In the case of PD-1 inhibitors, the direct target is PD-1, and the downstream target (i.e., the ligand of PD-1 that is affected by its binding) is PD-L1. In the case of PD-L1 inhibitors, the direct target is PD-L1. Recent results from studies of first-line treatment of advanced NSCLC with either nivolumab or pembrolizumab as a monotherapy demonstrate the potential value of PD-L1 as a biomarker in treatment of patients with PD-1 inhibitors.
PD-L1 as a biomarker has also been important in clinical studies supporting the approval of the PD-L1 blocking agent atezolizumab. Researchers found that increased PD-L1 expression in the tumors of patients with urothelial carcinoma was associated with response to atezolizumab. Although patients with tumors negative for PD-L1 expression might still respond to the drug, the greater efficacy of atezolizumab in those classified as positive for PD-L1 expression suggests that the level of PD-L1 expression in tumor-infiltrating immune cells may help identify patients more likely to respond to treatment with the agent.
Target biomarkers—especially PD-L1—are being used to define patient subsets that can productively be treated with a checkpoint inhibitor, especially in clinical trials and in approval decisions by regulatory agencies. However, these tests imperfectly discriminate between patients who can benefit from these therapeutics and those who cannot. Moreover, they are of little use in designing improved therapies that build on current checkpoint inhibitor therapies to improve patient outcomes.
Genetic biomarkers are also under investigation for use in cancer immunotherapy. In immuno-oncology, genetic biomarkers are generally used to determine the likelihood that a patient’s tumors possess a sufficient somatic mutation load to support a large and diverse population of CD8+ TILs, which are specific for mutation-associated neoantigens. Treatment with checkpoint inhibitors can then reactivate these TILs, resulting in effective antitumor immune responses. Examples of genetic biomarkers discussed in this report include mismatch repair (MMR) deficiency and mutation load, as determined by whole-exome sequencing.
Immunological biomarkers enable direct testing to determine whether a patient’s tumors contain sufficient TILs to enable successful treatment with a checkpoint inhibitor. In particular, researchers have found that CD8+ TILs located at the invasive margin of a tumor (as determined, for example, by quantitative immunohistochemistry) appear to be necessary for successful treatment with checkpoint inhibitors. In one study, researchers found that pre-existing CD8+ T cells located at the invasive margins of tumors from patients with metastatic melanoma may predict response to therapy with the anti-PD-1 inhibitor pembrolizumab. Patients who responded to therapy showed proliferation of the intratumoral CD8+ T cells that directly correlated with reduction in tumor size. The researchers established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent group of 15 patients.
Another type of immunological biomarker is the “Immunoscore”—a method of characterizing the nature and function of immune cell infiltrates into tumors based on measuring the densities of CD3+ and CD8+ cells in the tumor core and the invasive margin using immunohistochemistry. The Immunoscore was developed by Jérôme Galon, Ph.D. [Institut National de la Santé et de la Recherche Médicale (INSERM)] and his colleagues for use in studies of colorectal cancer. According to Dr. Galon’s findings, use of checkpoint inhibitors is the logical strategy for patients with high Immunoscores. In contrast, for patients with low Immunoscores, effective immuno-oncology treatments will need to focus on getting immune cells into the tumor in the first place (e.g., by treatment with a “second-wave” immunotherapy agent) before checkpoint inhibitors can be used.
Genetic and immunological biomarkers may be combined with target biomarkers and other parameters to move toward better discrimination between patients who are likely to benefit from checkpoint inhibitor treatments and those who are not. Specifically, biomarkers can be used to discriminate between “cold” and inflamed tumors. Genetic and immunological biomarkers can also be used to design therapies that can turn “cold” tumors into inflamed tumors, thus improving responses to checkpoint inhibitor therapy and other immunotherapies. For example, these biomarkers might be used to design combinations of treatments that induce immune infiltration of tumors with checkpoint inhibitors that activate or reactivate infiltrating immune cells, such as TILs. Novel agents that might induce immune infiltration of tumors are discussed in several chapters of this report.
More immediately, combination therapies involving the use of older treatments or agents, followed by administration of checkpoint inhibitors, are under clinical investigation to determine whether any of these older agents might render “cold” tumors inflamed, making them susceptible to checkpoint inhibitor therapy. Among these older treatments (discussed in Chapter 2) are radiation therapy (especially stereotactic body radiation therapy (SBRT), targeted therapies, and cytotoxic chemotherapies.
Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors
Various chapters of this report focus on approved and clinical-stage biologics other than the checkpoint inhibitors. Most of these agents may be used as “immuno-oncology 2.0” agents, i.e., agents that promote T-cell infiltration of tumors, thus rendering them susceptible to successful treatment with checkpoint inhibitors.
In addition to serving as an introduction to the report as a whole and discussing the early history of cancer immunotherapy, Chapter 1 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, M.D., Ph.D. (Dana-Farber Cancer Institute, 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 15–20% of patients and durable complete responses in 5–7% 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.
However, high-dose IL-2 has a significant degree of toxicity. Because of its adverse effects, high-dose IL-2 therapy for cancer requires an expert, experienced team of clinicians and specialized centers. Under such conditions of care, IL-2-related toxicity can usually be easily managed. Despite its logistical disadvantages, several investigators are attempting to revive use of IL-2 in cancer immunotherapy.
In the current era, it is possible to use targeted therapies as salvage agents to treat patients who do not do well with IL-2. There may also be opportunities to develop combination therapies of IL-2 with radiation or checkpoint inhibitors, and clinical trials of these combination therapies are underway. IL-2 treatment also requires only a median of one month of therapy and gives a long duration of benefit without the need for additional treatment. This is not true, for example, for treatment with cytotoxic therapies or targeted therapies. In addition to its use as a stand-alone drug, IL-2 is also used as part of certain cellular immunotherapies.
Other, newer cytokine-based therapies discussed in Chapter 1 are in early-stage clinical trials. Notably, local intratumoral electroporation of a DNA plasmid that encodes human IL-12 (pIL-12) (OncoSec’s ImmunoPulse) can result in systemic responses in metastatic melanoma patients. This procedure appears to induce TILs and anti-tumor immunity in both the injected tumors and in distant tumor sites. A Phase 2 trial indicates that intratumoral pIL12-electroporation therapy may prime systemic responses for checkpoint inhibitor blockade, apparently by generation of CD8+ TILs. ImmunoPulse therapy followed by treatment with a checkpoint inhibitor is therefore a potential immuno-oncology 2.0 therapy for metastatic melanoma. Other early-stage potential immuno-oncology 2.0 therapies discussed in Chapter 1 are based on the cytokines IL-10 and IL-15.
In addition to discussing approved and clinical-stage checkpoint inhibitors and their mechanisms of action, Chapter 2 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 PI3Kγ (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.
Chapter 3 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 (i.e., as immuno-oncology 2.0 agents). All of the agents discussed in this chapter are in early-stage clinical trials.
Chapter 4 discusses bispecific antibody (bsAb) cancer immunotherapeutics. A bispecific Ab (bsAb) is 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 close proximity. This allows the immune system to act against the tumor cell.
There are currently two approved and marketed bsAb cancer immunotherapeutics—catumaxomab (Neovii Biotech’s Removab) and blinatumomab (Amgen’s Blincyto). Catumaxomab is a rat-mouse hybrid bsAb that targets the tumor antigen epithelial cell adhesion molecule (EpCAM) and the T-cell surface molecule CD3. It is approved in Europe for treatment of malignant ascites in patients with EpCAM-positive cancer if a standard therapy is not available. Blinatumomab is a murine Ab-derived small bsAb that targets CD3 on T-cells and CD19 on B-cell neoplasms. It is approved under the FDA’s accelerated approval program for treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell ALL. It has also been granted conditional marketing authorization in the European Union for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL. Blinatumomab is the first anti-CD19 drug to receive FDA approval. As discussed in Chapter 6, the most advanced CAR T-cell (genetically engineered T cells bearing chimeric antigen receptors) therapies in development target CD19 and are intended for treatment of CD19+ B-cell leukemias and lymphomas. However, none of these cellular therapies is yet approved.