Gabriel Carabulea, M.D.

Board Certified Medical Oncologist 

Learning how to activate and harness the immune system – the bodies built-in defense against disease – has brought the field of oncology to the cusp of a cure for at least some, if not many types of cancer, according to James P. Allison, PhD., one of the international authorities in immuno-oncology and recent winner of the 2018 Nobel Prize in Physiology and Medicine. Dr. Allison received this prestigious prize for his research and launching of an effective new way to attack cancer by treating the immune system rather than the tumor. He was therefore one of those who have established an entirely new principle for cancer therapy. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of this approach in experimental models. His work eventually led to development of the first immune checkpoint inhibitor drug--ipilimumab (Yervoy)--approval for late-stage melanoma by the US FDA in 2011. The key that unlocks the potential of immunotherapy came in the form of discoveries about the activation and regulation of T-cells, which are at the very core of the human immune system’s disease fighting capability. The progress has continued and these days the pipeline of novel immunotherapies is expected to offer a more nuanced approach to cancer treatment, including ways to enhance the effectiveness of CTLA-4 and PD-L1 inhibitors by combining agents that facilitate the priming of antigen specific T-cells and synergize with immune checkpoint inhibitors. 

Because certain cancers are refractory to CTLA-4 and PD-1 blockade, researcher seek other targets that can harness an immunotherapy approach. New promising immunotherapy targets include TIM-3, LAG-3, and OX40. High expression of TIM-3 is associated with poor prognosis for prostate cancer, colon cancer, and urothelial carcinoma. In most tumor models, in vivo blockade of TIM-3 with other checkpoint inhibitors encouraged antitumor immunity and stopped tumor growth. OX40, a tumor necrosis factor receptor expressed by CD4 and CD8 T cells during antigen specific priming, has the ability to augment T-cell differentiation and cytolytic function which in turn can enhance antitumor immunity.

Genetically engineered or naturally occurring, oncolytic viruses selectively replicate in acute cancer cells without damaging normal cells. Oncolytic viral therapy has the potential to prime the immune responses. Modern technology these days enables us to identify the viruses that work the best. Researchers have evaluated pelareorep (Reolysin), a type of retrovirus in late stages of development for head and neck cancer. This is being also investigated and appears to work in other cancers as well. When the virus is given to a patient with relapsed myeloma, it increases expression of PD-L1 on myeloma cells. Researchers from MD Anderson Cancer Center have re-engineered a cold virus to make it into a potential anti-cancer weapon. Dr. So Sueyo and others have developed the "smart bump" virus or Delta-24, an adenovirus that is genetically engineered to replicate selectively in tumor cells. The fact that the virus would identify a pathway abnormal in cancer cells to replicate and kill is "smart" component of this strategy. This approach has been evaluated in a phase I clinical trial in 37 patients with malignant brain tumors with promising results. The evidence pointed out that infection of the tumor with Delta-24 elicited an antitumor immune response that was probably responsible for the elimination of the tumors. This is a paradigm shift in virotherapy. As a result, virotherapy is now considered one of the strongest forms of immunotherapy for solid tumors. The trial also showed that Delta-24 is not toxic and can be safely administered by injection into solid tumors. A new generation virus, called Delta-24-RGDOX, is expected to be more powerful than the parental virus in the awakening of the immune system. The combination of the Delta-24 with antibodies against anti-PD1 is currently being tested in a multi-center clinical trial (the CAPTIVE trial). Another direction being investigated is the potential use of oncolytic viruses in certain combinations. The viruses are likely not enough on their own, and likely require combination with other immunomodulating drugs to have optimal efficacy. 

The success of future immunotherapies also depends on biomarkers. Biomarkers will be essential for certain combinations. Currently the PD-L1 and tumor mutational burden are two more mature biomarkers that have been assessed in clinical trials and correlated with outcomes. Many other biomarkers are under development, such as T-cell receptor repertoire, circulating T-cells, infiltrating T-cells, neoantigen, interferon gamma, and inflammatory gene signatures, PD-L2 and other markers in the peripheral blood and at the tumor site. These biomarkers will help us to predict or select response, survival, or even toxicity more successfully. 

Recent research is suggesting that manipulating the microbiota may modulate cancer immunotherapy. T-cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanism underlying variable immune responses between individuals are not well understood. One possible modulator appears to be the intestinal microbiota. In clinical trials, oral administration of the Bifidobacterium alone improved tumor control to the same degree as PD-L1-specific antibody therapy, and combination treatment nearly abolished tumor outgrow in laboratory animals. It also augmented dendritic cell function leading to enhanced CD8+T-cell priming and accumulation in the tumor microenvironment. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ free mice receiving fecal transplant from responding patients. This data has important implication for the treatment of cancer patients with immune checkpoint inhibitors. This research is showing that factors beyond tumor genomics influence cancer development and therapeutic responses, including host factors such as the gastrointestinal microbiome. A number of studies have shown that the gut microbiome may influence anti-tumor immune responses by means of innate and adaptive immunity and that therapeutic responses may be improved through its modulation. This research has demonstrated significant positive correlation between the CD8 positive T-cells infiltrate in the tumor and abundance of the Faecalibacterium genus, the Ruminococcaceae family, and the Clostridiales order in the gut, and a non-significant but negative correlation with Bacteroidales. All this research is suggesting that altering the microbiome may be necessary to promote responses to checkpoint inhibition. This also explains the observation that administration of broad spectrum antibiotics significantly reduces anticancer effect of immune checkpoint blockades. Specific gut microbiomes may someday serve as biomarkers for identifying patients who might respond to checkpoint inhibitor therapy or be at risk of not responding or increased side effects. It suggests the potential merit of altering the patient’s gut microbiomes through probiotics, prebiotics, postbiotics, antibiotics, or fecal transplants to potentiate the efficacy and mitigate the toxicity of checkpoint inhibitors. Recent research has delved even deeper into the beneficial and detrimental effects of dietary components at the molecular level, examining how what we eat and drink influences the quantity and diversity of gut bacteria. These findings suggest that precision (personalize) nutrition might be utilized to favorably modulate an individual’s microbiota to reduce cancer risk. 

Immunotherapy has its own specific side effects. Checkpoint inhibitors can cause severe problems, mainly autoimmune illnesses in which the immune system attacks healthy tissue as well as cancer. Glucocorticoids are often used to treat immune related side effects and require a longer taper of 4-6 weeks. Immune checkpoint inhibitor related toxic events lead to death in about 0.3% to 1.3% of patients; this rate compares favorably with other treatment modalities. Colitis/diarrhea has been the most common toxicity among patients receiving ipilimumab monotherapy, followed by hepatitis and pneumonitis. Pneumonitis was the most common fatal toxicity in patients receiving anti-PD1/PD-L1 therapy. Myocarditis was associated with the highest risk of death. Ipilimumab-related deaths were dominated by colitis, whereas anti-PD1 had a wide spectrum of adverse events. The neurologic immune related adverse events are a lot more severe, refractory and prolonged, compared to the non-neurologic ones. The most common of these adverse events were neuropathy in 29% of patients, myositis and myasthenia gravis. ICI fatal toxicities are rare and seem to appear early in the course of treatment. With the increase in cancer survival, attention is now being paid to the question of when to stop therapy with these drugs. Treatment discontinuation studies, and longer follow up periods are needed before the treatment recommendations can be incorporated into survivorship care plans. Education is crucial. All patients and providers on the care team should receive immunotherapy education before, during, and after treatment. This knowledge and education can help caregivers and patients with early reporting of adverse events by recognizing the side effects and preventing long-term morbidity and late or permanent immune related adverse events. 

Immunotherapy is currently leading the revolution in cancer therapy that results in long-term survivors and should be kept in mind at the moment of planning any treatment regimen for cancer patients. Ongoing clinical trials hold the key to determining which of these novel immunotherapy will be the next big breakthrough for cancer research. Hopefully we will be able to come up with safer, more well-tolerated, and potentially more effective treatments in the near future.