Andre Goy, MD, chair, John Theurer Cancer Center, Hackensack University Medical Center and physician in chief for oncology for HMH Network, talks how immunotherapy continues to show promise for cancer patients.
Before we had immunotherapy, what were the treatments when a patient had lymphoma, when they had cancer?
GOY: Immunotherapy is changing the field of cancer and became the 5th modality of cancer care after surgery, radiation, chemotherapy and biological targeted therapies. Lymphoma is a great example of the succession of all these therapies over time – as it was treated initially with radiation and became the first tumor to receive chemotherapy, which was nitrogen mustard over 50 years ago. Then lymphoma became the first cancer to be treated with combination chemotherapy (i.e., putting several agents together). Then came the first monoclonal antibody rituximab targeting CD20 receptor at the surface of all B lymphocytes. Rituximab was used both alone and in combination with chemotherapy, leading to the next standard lymphoma regimens we have been suing since the late 90’s. The understanding of the biological diversity (i.e., cancer cells driven by different mechanisms or mutations) led to the new field of targeted therapies – which has dramatically expanded over the last 10-15 years. We can now in some indolent lymphoma or chronic forms of leukemia literally move away from chemotherapy using just combinations of some of these novel targeted agents, with impressive and durable responses with no or little toxicity, and taken as pills reducing the need to travel to cancer centers. The “new” field of immunotherapy spans actually several decades but has accelerated over the last decade from monoclonal antibodies, to checkpoint inhibitors (ie antibodies that can unleash the dormant immune system in cancer pts) and now CAR T cells which all have brought new options in lymphoma and leukemia even refractory to all standard therapies.
Talk to me about what our viewers hear, something like T cells and carti therapy. What is that, essentially?
GOY: CAR T cell stands for chimeric antigenic receptor – this is a complex word to say that these cells or lymphocytes (cells that make the immune system) are genetically modified to add a special receptor, which can force them to recognize cancer cells. These T cells are manufactured in the laboratory and expanded before reinfusion to the patient, where they expand further and kill cancer cells. This the first live therapy ever approved – now FDA approved in refractory / relapsed acute lymphocytic B-cell leukemia and in several subtypes of refractory / relapsed aggressive B-cell Non-Hodgkin lymphomas.
This is a very powerful therapy: one of these “armed” lymphocyte can kill 100000 cancer cells, leading to responses in 80-90% of patients, including complete response in 40 to 60% of cases. These responses have been seen even in patients who were totally refractory to their last therapy or who had failed over 10 prior different therapies. What is also remarkable is the duration of response with very few pts who relapsed after one year and then potentially cured.
I’ve heard it described as the killer cells. Is that an accurate way to think of this?
GOY: Yes – our immune system is equipped to kill cancer cells every day in all of us this is called immunosurveillance. The immune system is a complex and highly adaptive system organized in sort of “layers against the invaders”. Our lines of defense are multiple – they include cells that can absorb (engulf and literally eat) bacteria or cancer cells for example and then process them to activate the immune system; these cells are hence called macrophages. There are also several types of killer cells in our body including natural killer cells (NK cells) and cytotoxic T cells. The NK cells can recognize viruses and cancer cells without being primed and act swiftly – this why they are referred to as being part of the innate immune system; while cytotoxic T cells need to be activated and belong therefore to the adaptive immune system. Cancer cells – very early on develop ways to escape the immune system (to overcome the normal immunosurveillance mentioned above). They can do this by multiple ways: from hiding (not expressing molecules that would make them recognizable by killer cells) or instead overexpressing “teasers” for the immune system – which then becomes exhausted (and stop working). The immune reaction can be so powerful that is needs a delicate system of check and balances. Think about gatekeepers of the immune reaction or checkpoints, in cancer patients often the cancer cells have tricked the immune system by putting on breaks to let the cancer cells grow. All these different steps and types of cells represent opportunities to fight cancer. The foundation for immunotherapy in cancer is to restore the normal ability of the immune system to fight against cancer cells.
Again, they’re called killer cells?
GOY: So, the natural killer cells are the forefront. And we heard a lot about them during the news recently. They are the forefront of the immune system. They have the ability to recognize immediately viruses, cancer cells, and obviously we use it in patients. And then there some potential very promising therapy this way. But it’s also a use of cells we’re not sure to kill ourselves in as a tool to target cancer cells. And as you mentioned, kill yourself. This is one form of killer cells. The one that is more subject today is the the cartels and the cartels. He’s taking the other main type of cells of the immune system called t cells that are the cells that regulate, orchestrate the immune system. And they are made of cells that can help the immune system generate human response, stopping the immune response or kill the target. And what we do here, we genetically modified the patient’s own T cells by introducing a receptor that will then recognize once in a patient, put back in a patient and recognize the cancer cells here, the lymphoma cells. And he had a patient that we talking about to the mental cell lymphoma cells will actually go after and divide enormously and in the body and then kill the lymphoma cells. So it’s a first form of live therapy. It’s a genetically modified lymphocyte that we grow before we infuse. We inject in the patient. And then we monitor the patient. There’s a period when the patient receives this therapy that is really critical when you have critical, when you have to monitor this patient very carefully because they can have side effects related to the overreaction of the immune system. And there’s two main type of sound effects for our audience. One is called cytokine release syndrome is sort of the immunological storm that the T cells generate to try to further grow with these kinds of sort of a hormone of the immune system. And then you have the neurotoxicity, neurological toxicity. Every time T cells react strongly, they can actually affect their brain and go to the brain and we just sort of can create some confusion and create sometimes a neurological toxicity that can be pretty traumatic, but they all recover. The implication of this is that this has to be done very closely monitored and to in some situation, we can do it as an outpatient and more so than we do with inpatient for monitoring like a bone marrow transplant. Although it’s not a bone marrow transplant, we monitor patient very carefully and therefore can learn can mitigate those side effects.
Can you talk to me, Doctor, about the – you mentioned this type of cancer, that Alan had. Can you talk to me about that type of cancer? You had mentioned the receptors. There are a particular agent of receptors that was tested.
GOY: Of course, our patient here had mantle cell lymphoma, this is a rare subtype of lymphoma, about six percent of all lymphomas every year. But it’s a lymphoma that has generated a lot of interest in clinical research because the standard therapy, even high dose therapy used in relapsed aggressive lymphoma did not really work well in mantle cell lymphoma and patients typically continue to relapse and become more resistant over time. This creates obviously a challenge when you treat these patients, leading to a lot of innovative approaches and novel therapies over the last 2-3 decades. We have now thanks to these research efforts 6 novel therapies approved in relapsed or refractory mantle cell lymphoma: including 5 targeted biological agents (bortezomib, lenalidomide, ibrutinib, acalabrutinib and zanubrutinib) and more recently CAR T cells, which our patient here received because he had failed all other prior types of therapies. The CART cells in our case and all approved CAR T cells far have been directed at CD19 a molecule expressed in all B-cell lymphomas.
And that was my next question. Can you tell me a little bit more about the trial and.
GOY: The trial called ZUMA-2 trial – was the pivotal trial – that means the trial which served as foundation for the FDA approval. The normal T cells of the patient were taken from their blood (by a process called pheresis) and then modified and grown in the laboratory – before being returned to us for infusion. Meanwhile, just before infusion of these modified T cells – MCL patients received some very mild chemotherapy to reduce some “inflammation” in their body which could interfere with the growth of these T cells after infusion. Patients were then monitored in the hospital to manage potential side effects. As part of the rapid expansion of these eT cells in someone’s body, the immune system can go on overdrive in a way with high fevers, hypotension, malaise and confusion. This is the result of what is called the cytokine storm (CRS) and is often associated with some neurological adverse manifestations (headache, confusion, sleepiness, difficulty finding words, etc). The rapidly expanding activated T cells can go to the brain and be responsible of such manifestations. Although this is impressive – this is all reversible – and we have learned how to manage these by using antibodies to reduce inflammation (anti cytokine IL6 for example) or steroids.
The results of the trial were published in the New England Journal of Medicine showing 92% of patients responding, including 67% with complete disappearance of their disease. The toxicity was manageable and remarkably patients responded regardless of their number fo prior therapies. These responses were durable and at 1y 75% of the complete responses have been maintained. In our case Alan had a refractory mantle cell lymphoma, he is over three years out still in complete remission and potentially Alan could be cured.
Can you tell me a little bit more about the trial?
GOY: So this trial was a little bit over 70 patient that was presented for the first part of the trial. And so, we collect the cells of the patient. We modified the cells in the lab about 17 to 20 days later. We kind of reinforce the modified amplified cells to the patient and put them in the hospital and monitor them. Just before giving them those cells, we give them a little bit of chemotherapy to make sure their immune system would not slow down the amplification of those T cells, and then we monitor. So out of these 75-plus patients, the response rate was 93% – 93% of these patients responded. Sixty-seven percent of them achieved a complete response. What is the beauty of this cell therapy – and I’m a strong believer that, in the future, we’ll have less pills and more cell therapy. No question about this. What is the beauty of this is that we have some patients – typically, patients respond quickly. Median time to response is a month or so. So, patients respond quickly. We also had some patients that had a little bit of a delayed response, and it took them sometimes up to a year to convert into a complete response. So in the case of our patient, Alan actually had a Mendelssohn lymphoma, had failed all the standard lines of therapy, and came for these clinical trials. And he’s just over three years out and has been in complete remission and potentially Alan is cured.
You said he tried all of these other lines of defense. Was he truly out of options then before this?
GOY: Alan had his original diagnosis of mantle cell lymphoma in 2011 – 2012. He had a relatively aggressive presentation at the time and received high dose therapy followed by an autologous stem cell transplantation as a consolidation. In spite of this whole therapy, 18 months later he relapsed and he received bendamustine plus rituximab to which he responded but then progressed again. He received additional therapy followed later on by a BTK inhibitor called ibrutinib. BTK inhibitors have been really a game changer in mantle cell lymphoma because the responses are very impressive (80% of patients respond) and very durable with a very easy toxicity profile. So this became very much sort of the gold standard of relapse refractory mantle cell lymphoma. However, most of these patients, again, eventually relapse and have a very dismal outcome after BTK exposure. So Alan being three years out still in complete remission is fantastic.
Doctor, is there anything that you would want people to know about Car-T therapy and about treatments?
GOY: I think CAR-T cell therapy is something that has really had and will have an enormous impact on aggressive lymphoma and leukemia. We have now many ongoing trials in other lymphomas, myeloma and also solid tumors. There is no doubt in my mind that immunotherapy will become the leading form of therapy in cancer. There are many opportunities as mentioned above to tackle the immune system and restore the normal powerful ability of the immune system to kill cancer cells. The beauty of immunotherapy is the fact that when it works the responses ae very durable. The first patient who received immune checkpoint inhibitors for metastatic melanoma with brain mets on a clinical trial (at the time such patients who be sent to hospice) – is now well over 12 years out and in remission. The first patient who received CART cells for acute Leukemia I over 8 years out and doing well. Our next step is to learn more why some patients do well while others eventually do not respond or relapse after immunotherapy. We have ongoing research with Lombardi at GT and MSKCC looking at exactly this and trying to understand these mechanisms of resistance and this includes understanding better how the microbiome modulates and impacts some of these responses. Alan is a great example of the ongoing unprecedented changes happening in cancer care and we are very thankful and wholeheartedly embracing innovation – all our future patients rely on it and fully deserve it.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Mary Mcgeever
mary.mcgeever@hackensackmeridian.org
551-996-1730
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