With approximately 1639 drugs currently in clinical trials across the globe, immuno-oncology treatment — along with the personalised cancer vaccine — is on track to become the next breakthrough in oncology.1,2 Immunotherapy strives to enable the detection of a cancer mutation as an invader, thereby allowing the immune system to attack and eliminate a mutation in the same way as it would a pathogen. The ability to enable the immune system as the main defence in the fight against cancer has been in development for quite some time now, with the first monoclonal antibody, ipilimumab, gaining approval in 2011 for the treatment of melanoma.3 Since then, six have been approved, including CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor (ipilimumab), programmed cell death protein (PD-1) inhibitors (nivolumab, pembrolizumab) and programmed death ligand-1 (PD-L1) inhibitors (atezolizumab, avelumab and durvalumab).3 This growing field of oncology treatment is predicted to achieve steady growth going into the next decade.
Approaches to immuno-oncology
There are currently two approaches to immuno-oncology, either passive or active. Active immuno-oncology includes therapies such as cancer vaccines, cytokines and T-cell activation mediators that work to fight against tumours, as well as immunomodulatory mAbs.2,7 In active treatments, the tumour is targeted via an antigen presenting cell (APC); this antigen serves to stimulate an invader response in the immune system. In active immuno-oncology, therefore, the host’s immune system induces its own response.1 The immune system recognises the antigen, which elicits an internal immunity reaction. The immune system can also be triggered in a similar way through T-cell or innate cell simulation, which further serve to direct attention to the tumour and trigger the body’s active immunity.2
Immuno-memory defines active immunotherapy, which is promising when considering sustained remission. Active therapy is further divided into two categories, defined by a tumour-specific and non-specific response. In a tumour-specific response, the tumour is targeted through cytotoxic T-cells and humoral effectors.1 In non-specific active immunotherapy, a general immune response is triggered, although this is not necessarily related to the tumour. The agents in non-specific active immuno-oncology include interleukin-2, interferon-12 and Bacillus Calmette-Guerin (BCG). Interleukin-2 and interferon-12 are cytokines, whereas BCG is a bacterium responsible for tuberculosis.1
Passive immuno-oncology treatments are presented in the form of tumour targeting monoclonal antibodies or mAbs, oncolytic viruses, bi- and multispecific antibodies and other cell therapies or checkpoint inhibitors that directly target the tumour without necessitating an immunoresponse.1,2,7 As the name suggests, in this approach, the immune system plays a much more passive role, with the therapy working to directly attack the tumour cell without targeting a specific antigen.2 There is no immune memory in passive immunotherapy and, therefore, the timeline of treatment administration has yet to be defined, although it may be chronic.1
In passive immunotherapy, cytokines, checkpoint inhibitors or external antibodies — all of which are created in a lab — serve to provoke an immune response that will enhance a pre-existent immune response. This will create an immunity against the disease and produce an antitumour effect.
A treatment of particular interest in passive immunotherapy is adoptive transfer, which is commonly associated with monoclonal antibodies (mAbs). In adoptive transfer, immunocomponents create a specific response and bind to a protein in effector phase to stimulate an antitumour reaction. Although mAbs work through different mechanisms, some enhance the immune system’s response to the tumour by binding to the cancer cell, which allows the immune cells to spot and ultimately destroy them. This drug class also works by blocking growth factor receptor cell signals, thereby inhibiting the cancer cells from developing and/or spreading, such as with the Herceptin antibody, which inhibits the human epidermal growth factor receptor 2 (HER-2) proteins associated with breast cancer, as well as cancers of the stomach.
The cancer vaccine in application
This summer, the cancer vaccine passed a crucial test — albeit in a relatively small clinical trial. Six patients with melanoma skin cancer were treated with a vaccine injection, which targeted 20 predicted personal tumour neoantigens. These neoantigens were predicted through a machine learning approach to identify mutations (that would bind to autologous human leukocyte antigen [HLA] molecules) as well as the relative reliability of tumour coding sequencing.4 The researchers hypothesised that vaccinating participants with these neoantigens would result in the expansion of neoantigen-specific T cells, which already existed. In addition, they believed the injection would stimulate the creation of even more T-cells, with a broader range of specificities. Thus, this would make tumour control easier and more reliable, leading to the eventual treatment of the cancer.4
Their results were indeed substantial. According to the Nature paper: “Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively.” The T-cells were able to recognise the mutations, distinguishing between wild-type antigens and mutations, even targeting the autologous tumour specifically in some instances. Out of the six patients, four experienced remission, with no tumour or mutation reoccurring at 25 months after receiving the vaccine. Although the remaining two patients did have an incidence of the disease re-emerging, they were successfully treated using a passive immuno-oncology therapy (anti-PD-1). This led to a total regression of tumour production, as well as, according to the results, the “expansion of the repertoire of neoantigen-specific T cells.” This serves to further the need for an expanded study of the treatment options available in immuno-oncology, as well as their increased development. It is also recommended to devote additional research to a hybrid approach, mixing active and passive immunotherapies for a veritable “cocktail” of potential treatments.
Another success for patients with melanoma, again published this July in Nature, was the testing of an RNA vaccine to target the cancer.5 Using a personalised medicine approach, in which individual mutations were identified through a computational model outlining neoepitopes, scientists were able to create a unique vaccine, completely individualised to each patient. The results, published in “Personalized RNA Mutanome Vaccines Mobilize Poly-Specific Therapeutic Immunity Against Cancer,” details that out of the 13 patients to receive treatment, all expressed a T-cell response against multiple vaccine neoepitopes; this occurred at up to high single-digit percentages.
Overall, results were extremely positive. The research states: “The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival.” Of the total patients, eight were tumour free for more than a year after receiving the vaccine. Tumours shrank in three patients, although did emerge again for one. A third patient responded to the vaccine, and with a PD-1 inhibitor experienced full remission.5,6 The research concludes that this is an area of extreme opportunity, noting the full achievement of across-the-board results. “Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalised immunotherapy for patients with cancer.”
A hybrid treatment
Combination therapy may be key to the future of cancer treatment, as evidenced in both studies on melanoma, and taking into account the current oncology landscape. To completely eliminate the mutation, the immune system can be targeted at all phases of tumour progression, to ensure that the disease is unable to continue to spread. FDA has taken note of the potential for increased success when more than one therapy is introduced. In 2009, the agency approved bevacizumab and interferon-alpha, both used in the treatment of renal cancer. Together, the therapies produced a progression-free survival rate of 10.2 months as opposed to 5.4 in a control group exposed to only the interferon-alpha.7 Similarly, FDA passed nivolumab and ipilimumab in 2015 for the treatment of melanoma. When administered as a joint therapy, the progression-free survival rate was 11.5 months, as opposed to 2.9 months for ipilimumab and 6.9 months for nivolumab as a sole therapy.7 Whereas both of these drugs are defined as checkpoint inhibitors, their mechanism of action is on different regulatory pathways.
The most successful method of treatment is unlikely to involve just passive or active immunotreatments, but therapies that attack during each phase of the tumour cycle, ensuring its growth is kept in check. A cycle of treatment might resemble a step-by-step process. Begin with antigen release through a personalised, active cancer vaccine, and an oncolytic virus to directly kill the tumour cell and activate the immune system.
Follow this with checkpoint inhibitors to keep the tumour cell from growing and administer cytokines to further stimulate the immune system. An additional option would be to bring target cells to the tumour via BITE antibody constructs or bi- and multispecific antibodies — using cell-based therapy, reverse engineered to spot tumour cells, removing and reinfusing T-cells, and relying on mAbs to bind to tumour cells.7
Into 2020 and beyond
The entire immuno-oncology market is in a position to grow, and may emerge from being the fourth pillar in cancer treatment to the primary. In particular, checkpoint inhibitors have experienced rapid growth, increasing up to twenty times since 2010. The development and attention to the sector is additionally supported by the increase in trials.8
Analytics and data consultancy firm, Visiongain, estimates that the industry will command revenue of upwards of $16.55 billion during the next 2 years and into 2020, with that revenue predicted to further expand until 2026. The reason for this growth is in part because of a robust pipeline forecast for approval during the coming years.9 Mashael Zaidi, Industry Analyst at Visiongain asserted the potential for this segment of the market, noting: “The checkpoint inhibitor cancer treatment market only got off the ground in the past few years, but it is expected to continue to rise and change the landscape of cancer treatment. This market has already made strides in melanoma and NSCLC (non-small cell lung cancer) treatment. This trend will continue with further approvals for novel treatments that can offer something new, owing to their long-term duration of effect.”
He also noted the mechanism of action of these inhibitors, as the consumer segment will no doubt react positively to the potential of harnessing the body as an effective option in the struggle to find an effective cure. “Checkpoint inhibitors use the vast potential of the body’s immune response system and its countless connections to attack cancer cells in the body and use the immune memory cells to eliminate relapses,” he explained, continuing: “A recurrence of cancer cells in the body could be recognised and wiped out using this method and could leave healthy tissue alone, curbing side-effects and increasing the patient benefit-risk ratio. With this kind of potential, many companies have invested in the development of checkpoint inhibitors and the pipeline for these treatments is robust and has a promising future.”9
A market of full potential
Ultimately, as researchers hone in on the ability of the immune system to eradicate tumours, either by marking and attacking them with antigens or enhancing a previous immune response to disease, cutting off the growth receptors of a tumour — or a combination of these tactics and others — the potential for immuno-oncology appears to be quite bright. Traditional challenges in drug development, such as issues translating wide-scale results from mouse models to in-human clinical trials, as well as the costs and time associated with personalised medicine and developing unique, specific drugs are no doubt issues that must be overcome and addressed. However, aside from any possible roadblocks, the excitement and potential associated with harnessing a patient’s own immune system to completely eliminate cancer in a targeted approach is, ultimately, the most worthwhile reward. All forms of immuno-oncology therapies will progress in the coming years, and may become a primary course of treatment by the end of this decade.
- Global Data PharmaFocus: Visual Analysis of Immuno-Oncology Development and Opportunities: http://tiny.cc/6xqboy.
- www.nature.com/nature/journal/v547/n7662/ full/nature23003.html.