Cancer is a leading cause of death worldwide, accounting for approximately 8.8 million deaths in 2015. The number of cancer cases is expected to rise by about 70% over the next 20 years, creating a huge potential market for novel therapies.

Using the Immune System to Kill Cancer

The high number of genetic and epigenetic changes present in most cancer cells provides a plethora of tumor-associated antigens, i.e., proteins or other cell molecules characteristic of tumor cells that the host immune system could, in theory, recognize. However, the immune system has difficulties destroying cancer cells: sometimes because they aren’t different enough from normal cells, so the immune system does not recognize them as foreign; and sometimes because the tumors develop specific immune resistance mechanisms, so the immune response is not strong enough to effectively kill the cancer cells.

First approved by the US Food and Drug Administration (FDA) in the late 1990s, immunotherapy stimulates the immune system to target cancer cells. It has become an important component in treatments for various types of cancer, particularly blood cancers. The main types of immunotherapy now being used to treat cancer include monoclonal antibodies (mAbs), drugs against immune checkpoint inhibitors, and cancer vaccines.

Antibody-based therapeutics are one of the major components of therapies for cancer patients. Indeed, the two bestselling oncology drugs, accounting for $12.7 billion sales in 2015, are mAbs: Avastin (bevacizumab) and Herceptin (trastuzumab), both from Roche. Experts foresee that, in 2020, six of the ten bestselling cancer treatment drugs will be monoclonal antibodies, and this trend is expected to continue.

Examples of Antibody-Based Therapeutics

Our current knowledge of the molecular identities of many tumor-associated antigens and immune checkpoint mechanisms has allowed the development of antibody-based therapeutics, which take advantage of the specificity of the antibody-antigen interaction. For example, in an antibody blockade, the antibody binds strongly its antigen, thus blocking its function.

Some of the most commonly targeted tumor-associated antigens are growth factor receptors, which are overexpressed in a number of malignancies. These proteins promote tumor cell growth and insensitivity to chemotherapeutic agents. Monoclonal antibodies can diminish signaling, normalizing growth rates and resensitizing cells to cytotoxic agents. Some examples are trastuzumab (FDA-approved in 1998), an unconjugated anti-HER2/neu antibody, widely used alone and in combination with chemotherapy agents in breast cancer; and the anti-CD20 antibody rituximab (FDA-approved in 1997), used to treat lymphomas and potentially other malignancies.

Immune-inhibitory pathways, termed immune checkpoints, normally mediate immune tolerance and reduce collateral tissue damage, acting like “brakes” for the immune system. Tumors take advantage of some of these checkpoints becoming resistant to the immune system. A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte associated antigen 4 (CTLA4). Anti-CTLA4 therapy was the first agent to show a survival benefit in patients with advanced melanoma. It was therefore approved by the FDA in 2010, despite a high frequency of immune-related toxicity.

Other immune-checkpoint receptors, such as programmed cell death protein 1 (PD-1), limit T-cell effector functions within tissues. Many studies using mouse models of cancer have demonstrated enhanced antitumor immunity through antibody blockade of PD1 or its ligands. Importantly, studies in PD-1 knockout mice suggest that blockade of this pathway would result in less collateral immune toxicity than for CTLA4 blockade, which seems to be the case in the preliminary clinical trials. These trials suggest that blockade of the PD-1 pathway induces sustained tumor regression in various tumor types.

The results of both anti-CTLA4 and anti-PD-1 therapies have brought newfound awareness to the medical community about the potential antitumor activity of the patient’s immune system once the intrinsic brakes have been released.

Other antibodies currently in clinical development target receptor tyrosine kinases (RTKs), MAP kinase and PI3K/AKT pathways. These pathways play a key role in the regulation of proliferation, differentiation, and survival, and are also overexpressed in tumors.

Over the last few years, a novel class of anticancer drugs called antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering have led to highly potent tumor-targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market, and many others are in clinical trials.

Mechanisms of Action of Monoclonal Antibodies

Typically, monoclonal antibodies use a combination of mechanisms in directing cytotoxic effects to tumor cells:

– Mediating antibody-dependent cellular cytotoxicity (ADCC), where the antibody engages immune effector cells via the Fc receptors (FcR) on the surface.

– Triggering complement dependent cytotoxicity (CDC) in which the tumor cell is lysed by creating a pore in its cell membrane.

– Altering signal transduction within the tumor cell by downregulating important cell-surface receptors, like EGFR or VEGFR, reducing proliferation or inducing apoptosis.

– Delivering a payload (drug, toxin, radio-isotope, etc.) that causes cell death.

The transition from murine to chimeric and humanized antibodies (which contain human Fc domains) has allowed the optimization of the immunogenicity and the ability to recruit immune effector mechanisms. In the case of ADCC and CDC, it is desirable that the antigen-mAb complex should not be rapidly internalized in order to maximize the availability of the Fab region to appropriately engage with surface receptors, and of the Fc region to recruit immune effector cells and complement proteins, which can be done with an IgG1 isotype. In contrast, internalization is desirable for the mAbs altering signaling transduction, eliminating cell surface receptors or delivering a payload, in which case IgG2 is preferred.

Future Challenges and Perspectives

Although we currently have substantial knowledge of cancer biomarkers, one of the crucial challenges lies in defining the potential biomarkers that can determine which immune checkpoint pathways dominate in a particular tumor. This helps guide the choice of the treatment.

Another challenge is the clinical development of combinatorial approaches. Preclinical models validate dramatic synergy between tumor vaccines and inhibition of immune checkpoints. Anti-CTLA4 therapy strongly enhances the amplitude of vaccine-induced antitumor responses in many poorly immunogenic tumor models, as does anti-PD-1 therapy. Emerging studies demonstrate that targeted cancer therapies that are not conventionally thought of as immunotherapies (like vascular endothelial growth factor receptor (VEGFR) inhibitors and RAF inhibitors, among others) that can elicit or enhance antitumor immunity.

Much recent enthusiasm has been directed at the use of cancer vaccines—active immunizations designed to start an immune response to prevent or treat cancer. There are many ongoing trials and some pioneering marketed treatments, like Sipuleucel-T (Provenge), developed by Dendreon Corporation, which is a cell-based cancer immunotherapy for prostate cancer.

However, studies with melanoma patients show that T cells generated by cancer vaccines may not destroy solid tumors due to the inability to infiltrate and become activated after an encounter with tumor antigens in vivo. In contrast, promising results are obtained when immune cells generated and activated ex vivo are infused into the patient in a highly activated state, already displaying the necessary lytic and cytokine-secreting activities required to mediate the tumor destruction.

And finally, perhaps the next major breakthrough in cancer treatment after immune checkpoint inhibitors will be oncolytic virus therapy. It appears that it will not be long before this novel therapy becomes a standard therapeutic option for all cancer patients. The recent approval of Talimogene laherparepvec, or T-vec, (Imlygic, Amgen) in the US and Europe for the treatment of melanoma opens the door to oncolytic virus therapy. Also, a third-generation oncolytic HSV-1 virus, called G47∆, is already in phase II clinical trials for the treatment of glioblastoma in Japan. Many other oncolytic agents currently remain in development, providing hope that current success will be followed by other diverse vectors that may ultimately constitute a new class of clinical anticancer agents.

The enormous efforts taken by the research and medical community worldwide are yielding results and, ultimately, hope to all cancer patients. These novel types and combinations of treatments bring great promise to revolutionize cancer treatment regimes, allowing for tailored anticancer therapies that will be designed for each patient and will effectively eliminate each particular tumor.

Image courtesy of Simon Caulton.