Cancer Immunotherapy: A new strategy where the immune system’s Professional army is released to strategically battle with all its artillery and destroying tumor cells.
- Referring to trials with so-called ‘immune checkpoint inhibitors’. These drugs bring the tumor out from where it is hiding from the defense system.
- Tumor cells, by producing and presenting large quantities PD–L1 proteins on its surface, engage the PD1 protein on lymphocytes and as a result cancer cells evade the tumor destroying cells known as T lymphocytes.
- The antibody’s mission, used in immunotherapy, is to prevent this harmful union, which enables the defenses to release their safety brake, recognize the tumor as foreign once more and attack it
- Much personalized targeted medicine is based on therapies that block a particular aspect of each tumor molecular signatures.
- Immunotherapy could be administered in conjunction with those already existing or with others currently being studied, including chemotherapy, radiotherapy, targeted therapies or even vaccines, which would require several further studies.
- Today, more than 900 immunotherapy agents are in clinical development, and more than 1,000 in preclinical development, according to the Cancer Research Institute.
The role of the immune system in fighting tumours has been well-known since 1890 when it was discovered by chance, but it has taken more than a century to gain real importance. The journal ‘Science’ has chosen cancer immunotherapy as the most significant milestone reached in 2013.
Selective Immune-mediated tumor destruction is fascinating for science and tantalizing for oncologic doctors and patients, and in the last six years , researchers have found ways to point and manipulate the immune system’s destructive power in the direction of cancerous cells that have previously dodged detection. Clinical use of currently approved immunotherapeutics has demonstrated the power and durability of these therapies in a variety of cancer types, yet much work remains be done before science can realize the potential that exists to modulate the immune system. Today, more than 900 immunotherapy agents are in clinical development, and more than 1,000 in preclinical development, according to the Cancer Research Institute.
In 2017, there were 469 new trials initiated to test PD-1/L1 checkpoint inhibitors, a specific type of cancer immunotherapeutic, in combination with other drugs. Such trials may require patients of a specific immune status or genotype, potentially complicating recruitment and enrollment, especially if trial participants are drawn from a relatively small population of patients with specific biomarkers. Most current combination trials involving a checkpoint inhibitor exclude patients who have previously received the treatment that is to be evaluated.
In one of the elegant studies led by Ribas, included 135 patients who were treated with LAMBROLIZUMAB, an antibody directed against PD-1. This molecule is an Achilles’ heel in the defences that protect us against cancer, T lymphocytes (or T cells), which destroy tumour cells. When the PD-1 in lymphocytes joins to its complementary PD-L1, located on the surface of the cancer cell, a cascade of reactions occurs, which finally renders the lymphocytes incapable of performing their role. The defences are left powerless against the tumour, which can thus hide away from its constant surveillance.
This is where the lambrolizumab comes into action. The antibody’s mission is to prevent this harmful union, which enables the defences to release their safety brake, recognise the tumour as foreign once more and attack it. There is a change in the paradigm: The cancer is not attacked directly; rather, the immune system’s army is released to battle with all its artillery.
Overall, 38% of patients treated this way responded significantly to the treatment, and this percentage rose for those who received the highest doses. And, although not enough time has passed yet to draw any conclusions,
This lasting effect is key. Much personalized medicine is based on targeted therapies that block a particular aspect of each tumor, but in many cases the tumor reoccurs as it adapts to the treatment. In a way, this type of immunotherapy, which recruits a much more versatile army, able to recognize numerous enemies, enables cells with memory to be generated, which are retrained to attack the tumor.
The other significant study conducted by Memorial Sloan Kettering Cancer Center in New York and directed by Jed Wolchok. In this case they treated 53 patients with two different antibodies: nivolumab, against PD-1; and ipilimumab, against CTLA-4, another molecule implicated in inhibiting the immune system, whose use for melanoma has been approved since 2011, lung cancer and multiple myeloma.
The results were very similar to those of the previous study: 40% of patients responded to the treatment, a percentage that rose to 53% when administering the combination of doses that turned out to be the most effective. However, the side effects were notably greater as a consequence of autoimmune reactions. The immune system, now ‘freed’, attacked the patient’s own tissues.
Both of these studies are the backbones on which ‘Science’ justifies its choice. But what happened a year earlier was the real surprise. Ultimately, melanoma is a very specific kind of tumor. If this kind of immunotherapy were effective only for skin cancer, the breakthrough would be important but not revolutionary. It transpires, however, that another two Phase 1 trials published in 2012 used antibodies against PD-1 Or PD-L1 Tumor cells and other immune cells expressed inhibitory molecules that disabled T cells from recognizing and eliminating tumors. Patients with other kinds of advanced tumor have improvements like stomach, breast tumors, kidney or lung cancer did respond to the therapy. Although preliminary, these results are a real keystone and fuel the potential of these antibodies to act on a wide range of tumors.
Furthermore, this kind of immunotherapy could be administered in conjunction with those already existing or with others currently being studied, including chemotherapy, radiotherapy, targeted therapies or even vaccines, which would require several further studies.
Another issue will be the cost, as “they will almost certainly be expensive drugs,” Ribas muses. Although he adds that, from a broader viewpoint, “they might be cheaper in the long run, because treating metastatic cancer effectively and avoiding the greater costs that come with treating a significant portion of patients at terminal stages will save money.”
One cancer immunotherapy approach is to interfere with checkpoint mechanisms, such as PD-L1/PD-1 signaling, an interaction that inactivates T cells and spares cancer cells (A). When PD-L1 or PD-1 is bound by a checkpoint inhibitor, such as a monoclonal antibody, T cells stay activated, boosting the antitumor response
Harnessing Natural Killer Cells against Cancer
Natural killer are a subtype of lymphocytes with the power to release chemical that destroy the cell membranes of normal cells and tumors cells, destroying them and becoming one of the lethal cell machinery in the human body. During immunotherapy, research that leverages live cells to attack tumors is on the upswing, especially on the heels of FDA approvals of CAR-T cell therapy and wide use of checkpoint inhibitors. Yet, for patients who are immuno-depressed from a first-line treatment, T-cell-based therapy could face challenges, including obtaining functional T cells to modify or stimulate.
For applications like these, natural killer (NK) cell therapy is the next frontier. Varied immunotherapies have the potential to leverage NK cells’ ability to bind to and kill cells; approaches in development include bringing NK cells and cancer cells together through an antibody-based approach to cause direct cytotoxicity, or induction of antibody-dependent cell cytotoxicity.
“Humanized immune system animal models can support delivery of the human cytokines essential for NK cell survival, most notably human interleukin-15 (hIL-15),” notes Dr. Tanaka. Using a model that transgenically expresses human IL-15, investigators can engraft human donor-derived NK cells onto the model and use it for target validation studies.
Science is developing rapidly and significant contribution has been demonstrated during recent years in tailoring personalized molecular profiles for the control and treatment of cancerous cells.