Target Practice
Joseph Murphy

Target Practice

Along with the success in cancer immunotherapy, comes a growing need for well-characterized preclinical models.

Over the past three decades, conceptual and technical advances in the field of immuno-oncology have provided the knowledge and techniques to develop novel immunotherapeutic approaches that are demonstrating real clinical impact. Some of these advances will be on display at the American Association for Cancer Research conference opening Sunday in New Orleans. The most heralded new class of immuno-oncology drugs are the immune checkpoint inhibitors, which work by blocking the molecules that switch off immune cells, thus increasing tumor immunogenicity.

Among the immunotherapeutic methods being used in the clinic or explored for therapeutic potential are many that enhance tumor immunogenicity by blocking inhibitory pathways and inhibitory cells in the tumor microenvironment, such as antibodies against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed death 1 (PD-1) or its ligand programmed death ligand 1 (PDL-1). Similarly, methods that can enhance the specificity of anti-tumor immunity by inducing the expansion of T-cells and antibodies directed to well-defined tumor antigens are being investigated, such as cancer vaccines, potent adjuvants and immuno-stimulatory cytokines. Even as monotherapies, these approaches have a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. These successes provide a rationale to expect that future immunotherapies can transform cancer treatment, improving the prognosis for many patients, particularly those with hard-to-treat metastatic melanoma and prostate cancer.

With the increasing success and subsequent interest in cancer immunotherapy, there is a growing need for well-characterized preclinical models. We evaluated the responsiveness of several syngeneic murine tumor models to antibody-based, immune checkpoint inhibitor therapeutics targeting CTLA-4 and PD-1, and found a differential response across tumors when these inhibitors were used individually or in combination. This differential allows one to match efficacy with model and expands the portfolio of models available for evaluating combination therapies. Humanized mice are also beginning to gain traction in the study of immunotherapies.

We recently demonstrated the efficacy of checkpoint inhibitors in the human RKO colon carcinoma xenograft model in CD34-NSG humanized mice, which accommodate transplanted human tissue better than other humanized models. Results from these studies show significant tumor growth inhibition in response to checkpoint inhibitor monotherapies associated with activation of cytotoxic lymphocytes and cytokine expression. While checkpoint inhibitor treatment remains center stage in drug discovery, we still need to overcome the immunosuppression associated with cancer in order to achieve better immune-stimulation.

Moreover, other targeted and personalized treatment modalities will likely emerge. Central to this effort will be a reliance on appropriate preclinical models—the backbone of many immuno-oncology drug discovery programs—particularly in the study of combination therapy. Alternate strategies demonstrate different results in different patient populations. To improve clinical results early on in the discovery process, biomarkers that can identify the patients most likely to benefit from immunotherapy are actively being sought.

At the end of the day, it may be that the best results are obtained with vaccines in combination with a variety of antigens, or vaccine and antibody combinations. The combination of immunotherapy with conventional treatments (chemotherapy, anti-angiogenic therapy, etc.) should further improve this approach, both in its effectiveness and in its clinical indications.

How to cite:

Murphy, Joseph. Target Practice. Eureka blog. Apr 13, 2016. Available: http:/