A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline
By Jennifer Levin Carter, MD, MPH, Chief Medical Officer and Founder, N-of-One
In the past several years, great progress has been made in understanding the components of the immune system that are necessary for tumor control and in developing immunotherapies that help to more effectively fight cancer. Even when used as single agents in patients with advanced and rapidly progressive disease, some immunotherapies have demonstrated significant efficacy, suggesting promising potential for even greater efficacy if used in combination with other drugs and in earlier stage disease to effect long-term tumor control (Finn, 2012).
Many biopharmaceutical manufacturers recognize this significant market potential in immunotherapy and are aggressively expanding their pipelines (e.g., the recent acquisition of Costim Pharmaceuticals, a biotech company developing PD-1/PD-L1 inhibitors by Novartis).
Promising approaches in the development of immunotherapies and their associated mechanisms of action in the pipeline include:
- Immune Checkpoint Inhibition, and
- Adoptive Therapy
Immune Checkpoint Inhibitors
Immune checkpoint pathways downregulate immune system activity to minimize collateral tissue damage caused by the immune response. Some tumors have been shown to hijack these immune checkpoint pathways in order to develop immune resistance and evade the body’s immune cells. By inhibiting molecules involved in immune checkpoints, the immune system can receive a “boost,” allowing the immune cells to function more effectively to fight the tumor (Pardoll, 2012).
In 2011, Bristol-Myers Squibb’s (BMS) immune checkpoint inhibitor, ipilimumab (Yervoy), gained FDA approval for unresectable or metastatic melanoma. Ipilimumab’s approval was a milestone both in the treatment of melanoma and in the development history of immunotherapies.
Results of ongoing data involving 1,800 patients with melanoma treated with ipilimumab demonstrate that 22% of patients were still alive after 3 years. Following ipilimumab’s approval and subsequent success, a race began between manufacturers to improve upon this novel immunotherapeutic method.
Several therapies have already entered their final stages of development, which include BMS’s nivolumab, Merck’s MK-3475, both target PD-1 on T cells, and Roche’s MPDL3280A, which blocks PD-L1 on tumor cells.
Nivolumab is a monoclonal IgG4 antibody that blocks PD-1 on CD8+ T cells, tumor infiltrating lymphocytes (TILs), preventing PD-1 from interacting with PD-L1 (Creelan, 2014). In long-term follow up of a Phase 1 study of nivolumab in 107 patients with heavily pre-treated advanced metastatic melanoma, nivolumab demonstrated durable responses out to 2 years with a median estimated overall survival of 16.8 months and one- and two-year survival rates of 62% and 43%, respectively (Topalian, 2014).
In addition, 12 of 17 patients who discontinued the drug for reasons other than disease progression continued to respond to the treatment for at least 16 weeks and up to 56 weeks after discontinuation. The response rates in melanoma and toxicity profile of nivolumab compare favorably with those of ipilimumab and BRAF inhibitors (Topalian, 2014, Medscape 2014).
“In this study, even after the treatment was stopped, these responses continued,” said Suzanne Topalian, professor of surgery and oncology at the Johns Hopkins University School of Medicine, and director of the Melanoma Program at the Kimmel Cancer Center, in a statement to Medscape Medical News. “And without any further therapy, most of the patients remained in response for a very long time. In fact, one patient's tumor continued to shrink after the drug was stopped,” (Medscape, 2014).
Topalian explains that because the drug amplifies the immune response rather than targeting a specific mutation, it has the potential to treat patients whose cancers harbor many different types of mutations. In addition, although the best schedule for administration of PD-1 and PD-L1 blockers has not yet been determined, these therapies have the potential to emerge as a type of booster vaccine regimen, where patients may visit the clinic regularly to get their immune system boosted (Medscape, 2014).
BMS is currently conducting a series of Phase 3 trials (the Checkmate series) to further assess the efficacy of nivolumab, including two trials for NSCLC comparing the drug with docetaxel (NCT01642004, NCT01673867), one trial for advanced or metastatic clear-cell renal cell carcinoma compares it with everolimus (NCT01668784), and a study testing nivolumab in combination with ipilimumab for advanced melanoma (NCT01844505).
Merck’s MK-3475 is a highly selective anti-PD1 inhibitor. It is designed to block the interaction between PD1 and its ligands, PD-L1 and PD-L2, with the goal of restoring the immune system’s ability to recognize and target tumor cells. The drug received Breakthrough Therapy designation status from the FDA based on interim results from a Phase 1b study in patients with advanced melanoma (Merck, 2013).
In the study, 43 patients (out of 85 evaluable) showed an objective anti-tumor response, 8 of which showed complete response. In addition, 11 of 27 patients who had been treated previously with ipilimumab demonstrated an objective anti-tumor response (Merck, 2012). Last October, Merck released interim data from a Phase 1B trial evaluating MK-3475 in patients with previously treated NSCLC. In the 38 patient cohort the objective response rate was 24% based on immune-related response criteria (irRC) and a 21% rate by RECIST criteria (n=33).
The median overall survival at the time of analysis was 51 weeks with 7 out of 9 responders by irRC continuing on treatment, and the median duration of response had not been reached. High levels of PD-L1 expression were correlated with higher response rates than low levels (67% [6/9]) by irRC and 57% [4/7] by RECIST vs. 4% by irRC [1/24] and 9% [2/22] by RECIST, respectively]) (Merck, 2013).
Since the drug’s Breakthrough Therapy designation, a total of 16 clinical trials have opened assessing the efficacy of MK-3475 across various tumor types.
A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline (Continued)
The third closely watched inhibitor in development is Roche’s PD-L1 inhibitor MPDL3280A. At the 2013 European Cancer Congress (ECC), Roche presented an updated analysis of its original Phase 1 study in patients with advanced or metastatic NSCLC.
The results suggested rapid and durable responses in patients with heavily pre-treated locally advanced or metastatic NSCLC. Higher levels of PD-L1 by immunohistochemistry were predictive of response. The efficacy analysis was conducted in 53 of 85 patients; 23% of these exhibited a best objective response by RECIST criteria, and 11 of the12 responding patients continued to respond after the data cutoff. The 24-week progression-free survival (PFS) rate was 44.7%.
Based on these results, Roche has initiated two Phase 2 trials in NSCLC and is also investigating the combination of MPDL3280A with vemurafenib (Zelboraf) in patients with previously untreated BRAF V600E mutation-positive metastatic melanoma, and in combination with bevacizumab (Avastin) in patients with advanced solid tumors (Roche 2013).
Beyond Checkpoint Inhibition
Checkpoint inhibition is emerging as a powerful new therapeutic approach in the fight against cancer. However, simply blocking the pathway to immune cell suppression through checkpoint inhibition may not be enough to induce tumor shrinkage; additional immune system boosters may be needed (Pardoll, 2012). Researchers are exploring adoptive immunotherapy, a method that prompts the immune system to proactively attack tumor cells, as a method for inducing this “boost.”
Adoptive Cell Therapy: TILs, TCRs and CARs
Whereas checkpoint inhibitor therapies target the interaction that dampens the anti-tumor activity of lymphocytes (“taking the foot off the brake”), adoptive immunotherapies instead promote the activation of immune cells against cancer (“stepping on the gas”). Dendreon’s vaccine sipuleucel-T (Provenge), approved in 2010 for use in asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer, is the first approved drug in this class of immunotherapeutics. Unlike traditional vaccines that are developed against a generic antigen and administered to patients to raise an immune response in vivo, sipuleucel-T is individually customized to raise an immune response ex vivo with a patient’s own immune cells before delivering these cells back to the patient.
Although the precise mechanism of action of sipuleucel-T is not known, it appears that the antigen-presenting cells (APCs) that have taken up the fusion protein stimulate T-cells to attack tumor cells that express , prostatic acid phosphatase (PAP).
While sipuleucel-T is an example of a dendritic cell-based adoptive therapy, other adoptive therapies are in development as well, such as the Tumor Infiltrating Lymphocyte (TIL), T-Cell Receptor (TCR) and Chimeric Antigen Receptor (CAR) therapies.
Tumor Infiltrating Lymphocyte (TIL) Therapy
TIL therapy is highly individualized and involves culturing a patient’s own T-cells. The T-cells are harvested from a tissue sample taken from the area around a patient’s tumor. Data suggest that the cells near the tumor are likely to be “primed” for recognizing and attacking cancer cells. The T-cells are isolated, cultured, and then re-infused back into the patient together with the cytokine interleukin-2 (IL-2), a promoter of T-cell proliferation (Humphries, 2013).
Lion Biotechnologies is currently the forerunner in TIL therapy, having completed a study of 3 trials assessing the method’s effectiveness in heavily pretreated metastatic melanoma patients. The study assessed the efficacy of TIL treatment in 93 patients. All patients were pretreated with a non-myeloablative, lymphodepleting regimen of either chemotherapy alone or with radiation, followed by autologous TIL plus IL-2 treatment. TIL therapy led to complete regressions in 22% (20/93) of patients. Of the 20 complete responders, 19 continued to experience durable regression beyond 3 years (Rosenberg, 2011). Lion Biotech is also conducting pilot trials for TIL in combination with ipilimumab (NCT01585415) and soon with nivolumab.
Despite TIL therapy’s success in melanoma, this approach has not been successful in other cancer types. In addition, culturing T-cells ex vivo takes 4-6 weeks, a timeframe that is often too long for many patients with advanced cancer (Humphries, 2013).
T-Cell Receptor (TCR) and Chimeric Antigen Receptor (CAR) Therapy
Two additional adoptive therapies under early development for other cancer types include the TCR and CAR methods, which focus on modifying T-cells to attack cancer cells more effectively. The TCR method does this by adding a new tumor antigen receptor to the T-cells via a viral vector, or engineering the cells to promote their own growth. With TCR, the receptors must genetically match the patient’s immune type.
The CAR method avoids this issue by using artificial antibody-like proteins instead. Chimeric Antibody Receptors (CARs) are used to modify T cells for therapeutic effect. CARs use an engineered antibody fragment to recognize the target cell and link artificially to a number of signaling proteins within the T cell designed to activate the T cell after the antibody recognition fragment has bound to a target cell. However, in general, CARs are limited by the low number of antibody targets available on cancer cells (Adaptimmune, 2014).
The Key to Success: Discovering the Optimal Combination
Immunotherapy has long been studied for its potential to stop cancer from progressing by harnessing the power of the patient’s own immune system rather than attacking the cancer cells with cytotoxic drugs. After more than a decade of work, the approval of several immunotherapies with different mechanisms of action and the impressive data of from clinical trials on several novel therapies marks the beginning of a new paradigm in the treatment of cancer.
Researchers are investigating combination approaches with more than one immune therapy targeting different parts of the immune system, combinations with chemotherapy and targeted therapies, and different delivery mechanisms, including the use of biopolymers for timed and ongoing release of the therapeutic agent (Dolgin, 2013).
As with targeted therapies, there is a need to better understand why some patients respond and others do not and efforts are underway to identify predictive biomarkers. Despite these questions, it is clear that immunotherapy holds great promise for the treatment of many different types of cancer.
About the Contributor
Chief Medical Officer and Founder, N-of-One, Jennifer Carter, MD has been an early driver in shaping and delivering personalized medicine for oncologists at the point of care. Today, N-of-One is the leading provider of molecular interpretation and therapeutic strategies for oncology.
A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline (Continued)
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