Key Developments in Cancer Immunotherapy Over the Last Decade
Cancer immunotherapy has been heralded as the most promising advancement in the treatment of cancer since the discovery of chemotherapy. Immunotherapies for over a dozen types of cancer have been awarded regulatory approval, leading to a decline in the overall rate of cancer mortality in the US. In fact, the most recent available data from 2016–2017 reveals the largest ever recorded reduction in cancer-related deaths.1
This prior “decade of immunotherapy” commenced with the US Food and Drug Administration (FDA) approval for a cancer vaccine in 2010. The therapeutic vaccine Sipuleucel-T was shown to improve overall survival (OS) in patients with metastatic hormone-resistant prostate cancer.2 Furthermore, 2011 saw a landmark clinical trial for the use of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) targeted monoclonal antibody (mAb), ipilimumab, which led to the first FDA approval for a checkpoint immunotherapy.3
As the decade ended, the impact of immunotherapy on the cancer therapy landscape was highlighted by the award of the Nobel prize for physiology or medicine 2018 to Tasuku Honjo and James P. Allison for their ground-breaking work on the “discovery of cancer therapy by inhibition of negative immune regulation". The identification of the programmed cell death protein ligand 1 (PD-1) and CTLA-4 pathways has been integral to the production of a number of blocking antibodies with both FDA and EMA approval.
Current immunotherapeutic strategies consist of four main areas; checkpoint inhibitors, adoptive cell therapy, cancer vaccines and oncolytic viral therapy. Here we discuss the seminal immunotherapies of the decade and their impact on the future of cancer therapy.
Checkpoint inhibitors
The most notable checkpoint immunotherapy success stories center around the CTLA-4 and PD-1 pathways. CTLA-4 is a membrane-based protein receptor which binds to CD80/CD86 ligands on antigen presenting cells and functions as a negative regulator of the T cell mediated immune response.4 The monoclonal antibody ipilimumab targets the CTLA-4 checkpoint pathway and is regularly used to treat patients with melanoma,5 alongside promising clinical trials on a wide range of malignancies such as colorectal cancer6 and renal cell carcinoma7. The second anti-CTLA-4 mAb, tremelimumab, has been granted FDA approval for the treatment of mesothelioma as an orphan drug.8
PD-1 expression on cancer cells promotes regulatory T cell function and suppresses activation of CD8+ T cells. Two PD-1 mAbs, pembrolizumab and nivolumab, have been granted FDA approval for any metastatic or unresectable solid tumor identified by microsatellite instability or mismatch repair deficiency. Prior to this, no cancer drug approval had ever been granted based purely on tumor genetics.9 Promising Phase II/III clinical trials for other PD-1 mAbs such as avelumab, durvalumab and atezolizumab are currently ongoing.10
Checkpoint inhibitor therapies are, however, linked to a number of side effects that resemble autoimmune responses, and some patients will develop resistance, resulting in the progression of their cancer. Future strategies to improve clinical outcomes should therefore focus on not only novel agents but a number of combination therapy strategies.
Adoptive cell therapy
Adoptive cell therapy (ACT) involves the ex vivo expansion of cancer cell-reactive autologous lymphocytes and can be grouped into three main categories; chimeric antigen receptor (CAR) T cell, tumor-infiltrating lymphocyte (TIL) and engineered T cell receptor (TCR).
CAR T cell therapy involves the retroviral transfer of synthetically constructed hybrid receptors to autologous T cells. CAR T cells are able to recognize and respond to cancer-related antigens in a major histocompatibility complex (MHC)-independent manner, thereby opening a wider range of cancer types to ACT.11 The two ACTs that have currently been granted FDA approval are CAR T cell-based therapies. Axicabtagene ciloleucel targets CD19 on large B-cell lymphomas that have not responded to first-line treatment options,12 and tisagenlecleucel targets CD19 present on B cells in patients with acute lymphoblastic leukemia.13
TIL therapy comprises the ex vivo expansion and activation of naturally occurring T cells that have infiltrated neoplastic tissue. The majority of studies performed on TIL have been based on an advanced melanoma disease setting, including the Phase III randomized clinical trial comparing its use with ipilimumab.14,15 However, at present, the role of TIL in oncological standard treatment practice is yet to be determined. Engineered TCR therapy involves a similar process, with the addition of an engineered cancer antigen specific TCR to the autologous T cells.16 Promising clinical trials involving TCR therapy have mainly focused on melanoma and synovial sarcoma disease settings.17,18 Identification of cancer-specific antigens will be crucial to the improvement of TCR therapy safety and feasibility.
Since 2015, over 100 clinical trials on ACT have been initiated, which should provide a host of new breakthroughs for this treatment modality. The leading obstacle moving forward will be its successful translation to solid malignancies.19
Cancer vaccines
The clinical success of any promising cancer vaccine tumor antigen candidate relies on the presence of a number of features: a cancer cell-specific expression profile, expression of the antigen on all present cancer cells, an essential role in cancer cell survival and the ability to promote a vigorous immune response. Tumor-associated antigens (TAAs) are proteins expressed in healthy cells, which are abnormally expressed by cancer cells, and have been the target of choice for the majority of cancer vaccines to date. Examples of TAAs include; germline antigens, cell lineage differentiation antigens and antigens that are upregulated in cancer cells. However, a number of obstacles stand in the way of the successful development of a TAA vaccine; firstly, the vaccine must overcome both central and peripherally acquired tolerance of the immune system to such self-antigens. Several strategies, such as repeated vaccination, the use of adjuvants and co-stimulation have been employed to overcome this hurdle with varying results. Secondly, toxicity to healthy cells and tissue should be closely monitored, particularly as the potency of therapeutic cancer vaccines is developed. Conversely, neoantigens are derived from mutations in cancer cell proteins and are therefore not only cancer-specific, but also often profoundly immunogenic.20
Cancer vaccines can be divided into three main categories; therapeutic, preventive and personalized neoantigen cancer vaccines. Therapeutic vaccines target virally derived proteins expressed on infected cancer cells or TAAs. The first ever FDA-approved cancer vaccine, or immunotherapy of any sort was awarded in 1990 to the Bacillus Calmette-Guérin (BCG) tuberculosis vaccine, which was shown to act as an immune stimulant in the treatment of early stage bladder cancer.21 In 2010, FDA approval was granted to sipuleucel-T, which was shown to improve OS in patients with metastatic hormone-resistant prostate cancer by training autologous dendritic cells to recognize the antigen prostatic acid phosphatase.22,23 Preventative cancer vaccines restrict infection by viruses such as human papilloma virus (HPV), which is associated with the development of head and neck and cervical cancers, or hepatitis B (HBV) which is linked with liver cancer. There are currently four FDA-approved preventative cancer vaccines which target various strains of HPV and HBV.20 As mentioned above, neoantigens are solely derived from cancer cells. However, a large proportion of neoantigens are unique to each individual patient, and therefore necessitate the production of personalized neoantigen vaccine therapies. Several neoantigen therapies are currently being investigated.24
Oncolytic viral therapy
Oncolytic viruses are replication competent viruses that selectively target cancer cells over healthy cells. The use of such viruses in the treatment of cancer, particularly in combination with other available immunotherapies, is fast becoming an exciting reality. The therapeutic effect of oncolytic viruses consists of the direct oncolysis of cancer cells and stimulation of the patient’s innate and adaptive immune response.25 The first oncolytic virus to obtain FDA approval was Talimogene laherparepvec (T-VEC) in 2015. The virus was shown to generate a viral-mediated immune response in patients with advanced melanoma.26 T-VEC has also been assessed in Phase I and II trials for the treatment of pancreatic cancer and head and neck cancer, respectively.27,28 Oncolytic virus therapy represents a particularly promising role in combination with other immunotherapies that rely on the presence of robust anti-cancer lymphocytic populations, such as checkpoint inhibitors and cellular therapy. In fact, more than a third of the current ongoing oncolytic viral therapy trials involve their combination with immune checkpoint inhibitor drugs.
Conclusion
Huge advancements in the rapidly evolving field of cancer immunotherapy over the last decade have significantly improved our ability to successfully treat a wide range of malignancies. Combination therapies will be key to unlocking the full future potential of immunotherapies, particularly in conjunction with investigations into the mechanisms behind acquired resistance and advancements in the field of personalized therapies.
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