Friday, February 3, 2017

Will checkpoint inhibitors cure cancer?

Will checkpoint inhibitors cure cancer?

Checkpoint inhibitors such as pembrolizumab, nivolumab and ipilimumab have generated tremendous excitement in the field of oncology. Although there are many older tumor immunotherapy approaches that also work and have resulted in product approval, none of them have resulted in a similar level of enthusiasm. There are several reasons for this. Checkpoint inhibitors are conventional drug molecules in the sense that they are monoclonal antibodies, a class of drugs widely used in the past two decades. Also, their use fits well into routine oncology practice; nurses can administer them intravenously every 2-3 weeks. Also, in contrast to cancer vaccines for example, they give responses, meaning that tumors regularly shrink when the drug works, while some immunotherapy approaches exert their effect on survival, not tumor size. An advantage over “targeted therapy” is that a single molecular target is not required on cancer cells. Instead, checkpoint inhibitors “release handbrakes” on a body wide level and thus emergence of target-negative clones is less likely resulting in often a longer duration of efficacy. This body-wide effect also explains why these drugs frequently cause auto-immune adverse events. Finally, they are based on hard-core basic research, and the approach is sufficiently new not to seem like something that was already tried and did not work. Because of these reasons, mainstream oncology meetings have started to seem like immunotherapy meetings. Many of the most popular talks are on immunotherapy and checkpoint inhibitors hold the main stage therein.

With all this excitement, it can be forgotten that checkpoint inhibitors currently only work in a subgroup of patients. The frequency of responding patients might be among the highest in melanoma but even after careful patient selection only a third seem to respond to single agent checkpoint inhibitors while about half can respond to combinations of inhibitors, which unfortunately are much more toxic. In most other tumor types the frequency of responding patients appears to be lower than in melanoma and it is not yet known if similar long term survival effects will be seen.

Over the past couple of years it was discovered that checkpoint inhibitors only work in tumors where there is pre-existing antitumor immunity. Specifically, anti-tumor T cells need to be present. A simple T-cell staining might work as a useful biomarker, although more work is needed to understand how important the location and subclasses of T cells are. It probably makes a difference if the cells are intratumorally disseminated, at the invasive margin or just in the tumor periphery. There are many classes of T cells, some of which are suppressive. The difficulty in biomarker development is that representative fresh tissue is difficult to obtain and there might be big differences between different metastases and even within tumor masses.

The presence of anti-tumor T-cells appears to correlate with existence of neoantigens, proteins not encountered in normal cells. It is logical that foreign proteins resulting from de novo mutations would be more easily detected than self-antigens or overexpressed proteins. This may explain why melanoma, lung cancer and urological cancers seem to respond well to checkpoint inhibition. UV light in the former and smoking associated carcinogens in the latter two could explain the high frequency of neoantigens. Since any immune response will result in an immune suppressive counter-response (this is how the body protects itself against autoimmunity and normal tissue damage during immune cytotoxicity), the presence of tumor-reactive T cells and/or neoantigens correlates with mediators of immunosuppression, such as PD-L1. The currently most popular checkpoint inhibitors block the interaction between PD1 and PD-L1.

Unfortunately, when tumors lack neoantigens and the associated tumor infiltrating lymphocytes, checkpoint inhibitors don’t seem to work. In most cancer types the majority of tumors fall into this category. Can this situation be solved ? Certainly. There are powerful ways to induce T cells against the tumor. Some chemotherapeutics may be able to achieve this goal. Radiation can cause DNA damage resulting in neoantigens and subsequent T-cell activation. Some targeted therapies seem to result in T-cell infiltrates. Cancer vaccines may be able to induce anti-tumor T cells. However, possibly the most potent approach in this regard is the use of oncolytic viruses.

There are several reasons why oncolytic viruses are the perfect companion for checkpoint inhibitors. Virus replication lyses tumor cells releasing antigens (with different epitopes that are T-cell targets), whether they are intracellular or membrane bound. Viruses are the arch-enemy of the immune system, and actually one of two main reasons why we have cellular immunity in general (the other reason is bacteria). Nothing seems more dangerous to the immune system than viruses. Therefore, epitope recognition becomes more efficient when there are virus derived “danger signals” in the vicinity. The presence of virus can break tumor associated tolerance counteracting local immunosuppression. Tumors are heterogeneous, meaning that different antigens are present in different areas. The virus does not need to know about this; whichever epitopes are relevant are released as the virus penetrates into different areas of tumors. This happens spontaneously as daughter virions are released from exploding tumor cells. Some viruses including adenovirus are known to be able to travel through blood to metastases or reinfection of the same tumor.

Although viral epitopes are usually stronger than tumor epitopes, in fact they help in recognition of the weaker epitopes in a phenomenon known as epitope spreading. While oncolytic viruses per se are able to provoke anti-tumor immunity, they can be made more potent by arming them with transgenes. This field is still young but already some T-cell stimulating arming devices have been described, including interleukin-2 and tumor necrosis factor alpha.

In summary, while checkpoint inhibitors have provided much-needed excitement in the field of oncology, they only work in tumors with pre-existing T-cell immunity. Oncolytic viruses are the perfect tool for induction of such immunity, expanding the range of responding tumors. Emerging human data indicates that the combination is well tolerated as the virus doesn’t seem to add to the toxicity of checkpoint inhibitors and oncolytic immunotherapy in itself causes few side effects. Early efficacy result look very promising and in a few years we might have a combination approach which cures patients whose tumors are beyond current routine therapies.