Magazine Article | October 1, 2015

The Challenges Surrounding Immunology

Source: Life Science Leader

By Qian Shi, Ph.D., head of cancer pharmacology, Crown Bioscience

Immunotherapy is a growing trend within the oncology industry, as the traditional processes, methods, and equipment used in the fight against cancer are evolving and adapting constantly in order to try to find the most effective cure. Traditional treatments like chemotherapy and radiation remain effective methods of fighting the disease; however, recent research has started to shift away from aggressive indiscriminate treatments toward more targeted therapies.

It is well known that cancer has immune components; however, recent advances in research have shown that certain mechanisms of immune suppression of cancer can be reversed, resulting in the reactivation of the immune system to recognize the tumor cells and kill them. Traditional therapies are limited, as resistance can quickly arise; however, attacking a tumor with an activated immune system results in a durable response. Patients can survive longer and may even be considered cured, fueling demand for new therapies in this area.

There has been a recent upsurge in immunology due to the clinical success of checkpoint antibodies, such as anti-PD1/PDL-1, which restore immune function in the tumor microenvironment. Some of that success includes certain patients affected by difficult-to-treat cancers, such as melanoma or lung cancer, experiencing a long-lasting response, which is a striking outcome never observed before, thus driving the recent research expansion in this area.

There are three main trends in immunotherapeutic research, the first being diversification. Immunotherapy has become more diversified, leading to increased competition. Different mechanisms and therapeutics approaches are being explored, such as immune checkpoint inhibitors (such as anti-PD1/PDL-1 antibodies), adoptive cell transfer of T cells with chimeric antigen receptors (CAR-T), and tumor-infiltrating lymphocyte vaccines.

The second trend is combining immunotherapy with traditional treatments, such as radiation, chemotherapy, and targeted therapies. The aim is to widen the relatively small responder population of a certain cancer type and to expand the application of combined treatment to other cancer types that may not have been previously considered immunogenic. By combining traditional therapy with immunotherapy, researchers believe cancer cells will become more immunogenic and, as such, more easily recognized and attacked by the immune system, leading to better and more durable responses.

Finally, predictive biomarkers of response are increasingly being adopted to identify the patient population that is most likely to benefit from a particular treatment regimen.

Developing immunotherapeutics has various challenges, the biggest being identifying the appropriate animal models to evaluate efficacy and predicting toxicity in vivo. A lack of experimental models with a functional immune system for preclinical evaluation has significantly hindered immunotherapeutics’ development. Mouse syngeneic models, in which murine tumor cell lines are grafted into an immunocompetent murine host, are widely used to evaluate the efficacy of therapeutic molecules. However, this means that a molecule that targets a mouse model has to be used as a surrogate. Therefore, the translatability of the results is also debatable. Researchers have been working on developing humanized mouse models to address this issue, and although there are some promising results, most of the humanized models suffer from low reproducibility and lower efficacy due to the intrinsic complexity of these models. Furthermore, developing biomarkers for immune therapy, whether that is predictive pharmacodynamics or prognostic markers, has proved difficult due to the complex nature of this therapy and underlying mechanisms. With only a specific subset of patients benefiting from an immunotherapy agent, it is important to find those biomarkers for patient stratification, especially considering a patient’s immune system is complex and may evolve over time.

Advancements in immunotherapy are causing regulatory agencies to quickly adapt to the new scientific evidence and modify regulations accordingly. A good example is in clinical trials, where patients undergoing immunotherapy may experience an increase in tumor volume at the beginning of the treatment before tumor shrinkage. This is due to infiltration of immune cells into the tumor mass, resulting in an apparent volume increase, which under previous regulations and clinical criteria would have terminated the treatment. Other regulatory issues include the need to educate patients and physicians regarding potential toxicities of immunotherapy, which may depend on the type of treatment used. The treatment can be more aggressive and systemic, causing higher toxicity levels, but also a higher cure rate.

Regardless of these challenges, immunotherapy is a rapidly developing industry with striking results, which could transform cancer research and provide cures for a large number of people diagnosed with cancer.