Depending on the type of cancer, a specific treatment regimen can encompass one or more modalities such as surgery, radiotherapy, chemotherapy, and immunotherapy. In particular, cancer immunotherapy has generated considerable excitement within the research and pharmaceutical communities.

Recent FDA approval of several immunotherapies has validated the practicality of immunotherapeutic approaches and revitalized the field of immunotherapy. Unfortunately, a number of trials have revealed that only a subset of patients respond to immunotherapy. For this reason, biomarkers that can reliably predict patient response to treatment are needed to guide therapy decisions. Recent studies indicate that knowledge of the patient’s DNA repair machinery and mutational profile could provide the missing information needed to make these predictions.

What Is Immunotherapy?

Cancer cells can escape the immune system by hijacking it. Immunotherapy is a type of cancer treatment that is designed to strengthen or enhance the body’s immune system to fight the disease. In general, this can be achieved either by stimulating the immune system or training the immune cells, such as killer T cells, to specifically recognize and attack cancer cells. At present, immunotherapy can be classified into several approaches, which include monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, or non-specific immunotherapies that boost the immune system in a general way.

Cancer cells express several checkpoint proteins that are capable of engaging with immune cells, such as T cells and macrophages. By transducing specific signaling networks, they can shut down and/or delay the immune response. Examples of checkpoint proteins found on the surface of cancer cells include PD-1/PD-L1 and CTLA-4/B7-1/B7-2. Immune checkpoint inhibitors that work to prevent immune cells from being turned off by cancer cells have been heavily investigated as the next generation of cancer treatment.

The first successful clinical trial of an immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb), in metastatic melanoma was presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2010. This phase III, randomized, double-blinded, multi-center study demonstrated a significant survival advantage for the new monoclonal antibody targeting CTLA-4, which led to the subsequent FDA approval of ipilimumab for the treatment of melanoma.

Since then, the number of clinical trials examining immune checkpoint inhibitors has increased exponentially. However, it has also become clear that even though some patients respond positively to immunotherapy, a large percentage of them do not. There are multiple factors that affect the efficacy of checkpoint inhibition, which could lead to this result. One important reason appears to be whether the cancerous cells are recognized as foreign and targeted for killing.

DNA Repair Alterations or DNA Damage as Biomarkers for Immunotherapy

Genomic instability, manifested by a high frequency and magnitude of mutations, has been long recognized as a hallmark of tumors. This notion is particularly important in the field of immunotherapy, because mutated proteins presented by cancer cells can be immunogenic and evoke the immune response of the host. These proteins are sometimes referred to as cancer neoantigens, which are polypeptides that are recognized as nonself or foreign antigens, because they are usually not expressed on normal human cells.

Checkpoint blockade has been reported to be more effective in patients with a high mutational load (such as melanoma and non-small cell lung carcinoma) and less so in patients with lower mutational loads. In a recent PreScouter article, the potential of neoantigens was analyzed not only in the field of immunotherapy but also for the development of personalized cancer therapy.

As a reasonable next step, a new research priority has been to combine immune checkpoint inhibitors with agents that by themselves can induce DNA damage (which, as explained above, will increase the “foreignness” of the cancer cells). DNA damage can be achieved by several conventional cancer treatments such as chemotherapy (cisplatin, doxorubicin) and radiotherapy.

A few recent studies looking at the combination of tumor irradiation and dual CTLA-4/PD-1 blockade in melanoma have shown promising preliminary data. Similarly, the combination of cisplatin and checkpoint inhibitors show an encouraging efficacy in patients with non-small cell lung carcinoma. These initial studies set the stage for future upcoming studies that will hopefully expand the patient population who could benefit from immunotherapy in general, and checkpoint inhibitors in particular.

Conclusions

Immunotherapy treatments such as immune checkpoint inhibitors have been approved in multiple cancers and have provided significant improved survival and quality of life for patients. It has recently become clear that DNA damages or mutational loads have a major impact on the patient’s response to immunotherapy because of the observation that DNA repair deficiency is often associated with high mutational load and positive immunotherapy response. As noted here, progress has been made in utilizing this information to improve the efficacy of immunotherapy treatments.

Nonetheless, recent studies show that a more stringent understanding of the interaction between the immune system and DNA repair machinery is urgently needed in order to identify key mutations that are sufficient to predict the success of immunotherapy. Technological advances, such as whole exome sequencing, and formation of several international data-sharing platforms, such as the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE), will undoubtedly accelerate the process and improve the clinical efficacy of immunotherapy.