April 2014 Edition Vol.11, Issue 4

A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline

A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline (Continued)

Roche’s MPDL3280A

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.

www.n-of-one.com

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