Modern Immunotherapies Known as Checkpoint Inhibitors
- 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.
- These drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma.
The role of the immune system in fighting tumors 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.
An important part of the immune system is its ability to tell between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells while leaving the normal cells alone. To do this, it uses “checkpoints” – molecules on certain immune cells that need to be activated (or inactivated) to start an immune response.
Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints hold a lot of promise as cancer treatments.
Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. These drugs have shown a great deal of promise in treating certain cancers.
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 to 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.
PD-1 inhibitors: Examples of drugs that target PD-1 include:
- Pembrolizumab (Keytruda)
- Nivolumab (Opdivo)
These drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer.
PD-L1 inhibitors: Examples of drugs that target PD-L1 include:
- Atezolizumab (Tecentriq)
- Avelumab (Bavencio)
- Durvalumab (Imfinzi)
n 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 defenses that protect us against cancer, T lymphocytes (or T cells), which destroy tumor 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 defenses are left powerless against the tumor, 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 defenses to release their safety brake, recognize the tumor 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.
Finally, oncology, has moved toward incorporating molecularly targeted therapeutics directed toward individual genetic abnormalities in tumors, so-called precision medicine. In ovarian cancer and primary peritoneal cancer, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) has emerged as an important target, particularly for women with BRCA gene pathway mutations. We describe a recently published randomized controlled trial of the PARP inhibitor Niraparib.
Precision medicine, targeted therapies in oncology
Precision medicine refers to the customization of medical therapy based on the genetic characterization of the individual patient or the molecular profile of the patient’s tumor. As a result of large-scale molecular profiling from projects such as the International Cancer Genome Consortium and The Cancer Genome Atlas, an abundance of molecular data has been generated through the characterization of multiple tumor types. This has led to the discovery of key cancer drivers, alterations, and specific molecular profiles that have distinct prognostic and treatment implications. These data, in combination with the commercial availability of molecular profiling tests, has made precision medicine a reality for women with ovarian cancer.
This wealth of new information has led to the development of targeted therapeutics that block the growth and spread of cancer by acting on specific molecules or molecular pathways. Targeted therapies approved for cancer treatment include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, and immunotherapies
How PARP inhibitors work
PARP inhibitors are a class of agents that are emerging as important therapies for ovarian cancer. These agents block the nuclear protein PARP, which functions to detect and repair single-strand DNA breaks with the resulting accumulation of double-stranded DNA breaks.15 In the setting of DNA damage, the homologous recombination repair pathway is activated for repair. However, homologous recombination deficiencies (HRD) can arise as a result of BRCA1 or BRCA2 mutations or BRCA-independent pathways, which effectively disable this DNA repair pathway.
As a result, when PARP inhibitors are used in patients with HRD, the cell cannot repair double-stranded DNA breaks and this leads to “synthetic lethality.” in other words, This action may keep cancer cells from repairing their damaged DNA causing them to die. Understanding this molecular mechanism of PARP inhibitors as well as the frequent abnormalities in the BRCA genes and HRD pathways in ovarian cancer has provided an important potential therapeutic target in ovarian cancer. A number of PARP inhibitors are now commercially available
and are undergoing testing in ovarian cancer– Rucaparib and Niraparib are typical PARP inhibitors
Niraparib for ovarian cancer: In a randomized, double-blind, phase 3 tria by Mizra and colleagues, 553 women with platinum-sensitive recurrent ovarian cancer who responded to therapy were divided according to the presence or absence of a germline BRCA (gBRCA) mutation and randomly assigned to niraparib 300 mg or placebo once daily. Women in the niraparib group had a significantly longer median duration of progression-free survival than
did those in the placebo group. This was most pronounced in women in the gBRCA cohort (21.0 vs 5.5 months). Importantly, niraparib was associated with improved progression-free survival in HRD-positive patients without gBRCA mutations (12.9 vs 3.8 months) as well as in the HRD-negative subgroup (6.9 vs 3.8 months). Overall, niraparib was well tolerated. About 15% of women discontinued the drug due to toxicity. Significant (grade 3 or 4)
adverse events were seen in three-quarters of women treated with niraparib, and they most commonly consisted of hematologic toxicities. Patient-reported outcomes were similar for both groups, indicating no significant effect from niraparib on quality of life.
This study’s results suggest that niraparib has clinical activity against ovarian cancer. Importantly, niraparib was active in women with gBRCA mutations, in those with HRD without a gBRCA mutation, and potentially in women without HRD. If approved by the US Food and Drug Administration, niraparib will join olaparib and rucaparib as
a newly approved therapeutic agent for ovarian cancer. This study provides important evidence that suggests niraparib maintenance therapy may be an efficacious and important addition to the treatment armamentarium for platinum-sensitive ovarian cancer.
The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.
- American Cancer Society
- The National Cancer Institute
- National Comprehensive Cancer Network
- American Academy of Gastroenterology
- National Institute of Health
- MD Anderson Cancer Center
- Memorial Sloan Kettering Cancer Center
- American Academy of Hematology