How Immunotherapy Makes a Real Difference in Relapsed Hodgkin Lymphoma
Hodgkin lymphoma, which affects about 0.2% of the people in the United States, is often treated using a combination of chemotherapy, radiation therapy, and stem cell transplant. Sometimes these treatments fail to halt the progress of the disease, and in other cases the cancer seems to halt but then relapses.
There is another treatment that is available for treating Hodgkin lymphoma, however. This is the use of immunotherapy. Immunotherapy is the use of the immune system, either by bolstering it, triggering it to act, or even suppressing it to allow other treatments to act more efficiently.
Immunotherapy and Hodgkin lymphoma
This is important because sometimes the disease initially responds to treatment but then returns, in which case it relapses. In other cases, the cancer is refractory, which means that it resists the normal treatment for the disease.
Here is where immunotherapy comes into play. The use of immunotherapeutic methods can help provide improved treatment for people with diseases such as Hodgkin lymphoma which have either relapsed or have resisted treatment.
Immunotherapy has been used to help treat relapsed Hodgkin lymphoma, but there have been few studies on the overall effectiveness, especially when the Hodgkin lymphoma has relapsed.
Javie Briones, MD, PhD, the chief of the Hematology Service at the Hospital de la Santa Creu I Sant Pau in Barcelona, Spain, looked into this. He spoke about his results at the 2nd Annual European Congress on Immunotherapies in Cancer™, which was hosted by the Physicians’ Education Resource®, LL.
The immunotherapies investigated
Three immunotherapeutic drugs were investigated. These were brentuximab vedotin (Adcetris), nivolumab (Opdivo), and pembrolizumab (Keytruda).
The first one, brentuximab vedotin, is an antibody-drug conjugate. It targets something called CD30 and delivers a cellular toxin. The other two are checkpoint inhibitors, which sneak past the cancer cell’s stealth to allow the antibody to perform its duty. They target PD-L1.
CD30 and PD-L1
CD30 is a protein also known as TNFRSF8. It is in the tumor necrosis factor receptor family is a marker of tumors. One of the diagnoses of Hodgkin lymphoma is that the tumors express CD30; without CD30, it is not Hodgkin lymphoma.
PD-L1 is another protein. The name also means “programmed death-ligand 1.” Its purpose is to suppress the immune system during pregnancy. This beneficial interaction is twisted by certain cancers, such as Hodgkin lymphoma, to allow the disease to hide under the radar of the immune system.
Antibody drug conjugates
These types of medications are also called ADCs. They hold a large advantage over standard chemotherapy methods, because ADCs are targeted. They are designed to affect only the cancer cells, and unlike chemotherapy do not have an effect upon the body as a whole.
ADCs accomplish this task by being a combination, or conjugate, of both antibodies and cancer-killing drugs. Those drugs are also called cytotoxins. Linkers are used to combine the two.
The antibodies used are typically unable to destroy cancer cells on their own, but they are still capable of tracking them down by following certain proteins. They then react with the cell producing those proteins, the cancer cells, and are absorbed by the tumorous mass.
This is when the cytotoxin comes into play. The biomechanical reaction which absorbs the antibody also causes the linker to separate from the cytotoxin, which allows it to wreak havoc upon the cancer cell.
Because the antibodies target one specific protein there is a low chance of the ADC attacking the wrong type of cell. Therefore, ADCs cause fewer side effects than the nuke-them-all mechanism of chemotherapy. They also tend to last longer in the body.
Checkpoint inhibitors
The other type of medication examined were checkpoint inhibitors. These utilize antibodies which could themselves attack the cancer cells, but are blocked from doing so by a protective signal produced by the cancer cell.
Both of the checkpoint inhibitor style medications investigated were cleared for use relatively recently, as recently as May of 2017 in the case of pembrolizumab.
Checkpoint inhibitors are not as free of side effects as are ADCs, because the body naturally expresses PD-L1 more often than CD30. It is especially dangerous for use with pregnant women as PD-L1 is produced to prevent the mother’s immune system from attacking the baby.
But they can be used when the cancer is so effective at hiding itself that drugs that target CD30 cannot find their target. Checkpoint inhibitors also show promise as single agents, which would allow the body to defeat cancer without the addition of chemotherapy or radiation therapy.
However, another downside is that only 90% of Hodgkin lymphomas express PD-L1, unlike the 100% expression of CD30.
The efficacy of brentuximab vedotin
There were two phases of research into brentuximab vedotin. The first was a review of 102 patients, all of whom had refractory Hodgkin lymphoma or had relapsed. Each one had received autologous stem cell transplantation, and on average each patient had received 3.5 chemotherapy regimens.
71% of those patients had been refractory to those therapies; the treatments had been ineffective. The rest had relapsed. Each patient was then given immunotherapeutic doses of brentuximab vedotin.
Three quarters of the patients responded to the drug. 40% of the people given the drug (not 40% of the people who responded) only had a partial response. 34% had a complete response (the remaining 1% is not mentioned). Of those, 9% had such a good response that they did not require any further treatment whatsoever.
In response to this result, Briones said, “so we can say that at least 9% of those patients were probably cured with just brentuximab monotherapy.”
The second phase use different patients who had just received autologous stem cell transplantation. They were randomly given either brentuximab vedotin or a placebo. They examined how long treatment lasted before the cancer ceased to progress.
On average, the patients on the placebo took almost twice as long until their cancer’s progression had been halted; 43 months instead of 24 months. The researchers also noted that the benefit was stronger in patients who had a higher chance of a relapse.
The efficacy of checkpoint inhibitors
The research into checkpoint inhibitors is younger than the research for ADCs, and as such some of the studies are ongoing. The prognosis seems good.
One study involved patients who had relapsed or refractory Hodgkin lymphoma and who had been administered the stem cell treatment and brentuximab vedotin already. Nivolumab became their next treatment. On average, the time before the patients became free of cancerous progression dropped to 10 months.
Another study is still in progress, but results are already being seen. Nivolumab is being administered alongside brentuximab vedotin to patients with relapsed or refractory Hodgkin lymphoma. The response rate is already 85%, and the complete response rate is 64%, even though the study has not yet reached its conclusion.
The side effects
These types of immunotherapy are, sadly, not without their own side effects. Two of the most common reported were cytopenia and fever. Cytopenia is when the amount of mature blood cells are low, regardless if they are white blood cells, red blood cells, platelets, or granulocytes.
The most feared side effect, cytokine release syndrome, was thankfully not reported. This is when large amounts of immune system cells become activated and release their cytokines regardless of whether it’s into a cancerous cell or not. This leads to widespread systematic inflammation.
This nasty side effect has shown up from other immunotherapeutic methods. In severe cases it can lead to a cytokine storm, where the inflammation causes the white blood cells to release more cytokines in a positive feedback loop!
The fact that this does not happen as a result of these therapies is, understandably, a welcome discovery.
Something else notable about the side effects is that when ADCs and checkpoint inhibitors were combined, the amount of side effects did not increase to a significant degree.
Final thoughts
Part of the reason why cancer can be such a nasty disease is that it subverts the body’s own immune system. Older therapeutic methods use indiscriminate methods which damage both the cancer and the healthy cells.
Immunotherapy allows the body’s immune system to fight back, arming the antibodies with the biological equivalent of smart bombs. These therapies show promise in not only fighting Hodgkin lymphoma, but is annihilating the forms of this cancer which resist more traditional treatment methods.
References
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613712/
