Cancer immunotherapy is currently at the forefront of emerging therapies for the effective treatment of multiple types of malignancy. Many immunotherapy agents such as checkpoint inhibitors (nivolumab, ipilimumab etc.) have been demonstrated to promote reductions in both tumor burden and disease recurrence, and many results from the recent ASCO meeting continue to support the notion that cancer immunotherapy has ‘come of age’.
We recently talked to Professor Shimon Slavin from the International Center for Cell Therapy & Cancer Immunotherapy (Tel Aviv, Israel) about the other side of cancer immunotherapy, discussing his innovative work in stem cell transplantation and donor lymphocyte infusion, with the ultimate aim of curing cancer patients.
What first sparked your interest in cell therapies?
For many years I was interested in the topic of stem cells because they can be a source of different subsets of cells. By using stem cells you can therefore treat and even cure a very large number of malignant and nonmalignant diseases that are otherwise incurable.
Can you tell us a little about your career and what led you to where you are today?
First of all I started to work with hematopoietic stem cells, investigating their use in curing otherwise lethal diseases through stem cell transplantation. These include diseases caused by deficiency of bone marrow products like aplastic anemia, ‘bubble babies’ who are born without an immune system, genetic diseases, autoimmune diseases and the largest use in cancer – predominantly in hematologic malignancies but also occasionally in solid tumors such as neuroblastoma in children, and breast cancer and renal cell cancer in adults. All you have to do is prevent rejection of the bone marrow cells, and if you can do that successfully then the patient will incorporate the stem cells of the donor and will start producing normal cells.
In cancer cases there are two possibilities for cure. One is to give patients very high doses of chemotherapy and radiation therapy in an attempt to kill all the malignant cells, which you cannot do with conventional doses of either, and then rescue the patient with stem cells. If the treatment was good enough to kill all the cancer the patient may be cured. However, this is not an intelligent way to cure cancer, because in order to do that you have to use lethal doses of chemotherapy or radiation. This of course is a very risky procedure and it cannot be applied to elderly or very sick patients. When applied for treatment of children, sterility, bone growth impairment and multiple endocrinopathies are unavoidable. Even then, recurrent disease continues to be the single cause of failure, while in parallel procedure-related toxicity and mortality is also unescapable. That is the way things used to be before we changed the whole philosophy of stem cell transplantation.
Around 28 years ago we were the first to show that donor lymphocytes are the main reason why cancer can be cured following stem cell transplantation. The first patient we treated had failed his stem cell transplantation for fully resistant leukemia. He received supra-lethal doses of chemotherapy and radiation in an attempt to kill the leukemia, but 2 months later he came back with wall-to-wall disease, with leukemia blasts infiltrating his blood and marrow and even causing tumor masses. One obstructed his airway meaning an emergency tracheotomy was unavoidable. This, like other patients with advanced resistant disease, proved that even ‘atomic bomb treatments’ could not eliminate all of the malignant cells. We decided that because the patient had previously accepted stem cells from the donor he would now accept donor lymphocytes, so we gave him one syringe (20 ml) of blood from the donor and sent him home. A week later he was still alive, so he was brought in again and given another 20 ml of blood. We administered similar injections six times. Surprisingly, within the next few weeks the tumor started to regress and finally disappear. The patient is now alive and well, 28 years later with no evidence of disease.
This patient was the first proof that lymphocytes of the donor could induce anticancer effects that can be more powerful than maximally tolerated doses of total-body radiation and chemotherapy. Initially, nobody believed me that lymphocytes present in six syringes of blood could do something that no chemotherapy or radiation therapy can do, but then we repeated similar procedures and showed that this was a consistent effect, now called donor lymphocyte infusion (DLI). We cannot expect to cure every patient, but we can cure a lot of patients with recurrent disease or prevent disease recurrence in patients at high risk of relapse that otherwise would be dead just by immunotherapy based on the use of donor lymphocytes.
We then showed that the anticancer effects of DLI could be maximized by activation of donor lymphocytes with a compound that can activate lymphocytes, IL-2. We could also increase selectivity and efficacy of DLI by targeting anticancer effector cells with specific antibodies against antigens expressed on the cell surface of cancer cells, a procedure known as antibody-dependent cell-mediated cytotoxicity.
Next we considered: “If lymphocytes could kill better than the ‘atomic bomb treatment’, why do we need to subject a patient to this dangerous treatment at all?”
Such an aggressive treatment is not suitable for sick patients in poor performance status or patients above the age of 50 or 60 years; however, most of the indications for stem cell transplants are for individuals above the age of 60 years. We did the opposite to conventional treatment: instead of maximizing radiation or chemotherapy in order to kill more cancer cells, we minimized the intensity of treatment, focusing on agents sufficient to supress the immune system of the patient in order to make it possible to accept donor stem cells.
Once the patient accepts the donor stem cells they become tolerant to the donor, meaning it is possible to transfer donor lymphocytes without them being rejected. The ‘cure process therefore occurs after transplantation, mediated by circulation of the donor lymphocytes present in the bone marrow or by additional donor lymphocytes administered later on. Instead of trying to kill all tumor cells before transplantation, using the transplant procedure induces transplantation tolerance and lets donor lymphocytes do the job. If the disease comes back or if the patient is a high-risk case, DLI can be used either to treat early relapse or to prevent relapse. We therefore changed the transplant procedure into an immunotherapy protocol – we can now accept patients of all ages and sometimes accomplish the procedure without even putting them in hospital, by carrying out the entire procedure on an outpatient basis. The procedure is called nonmyeloablative stem cell transplantation or reduced intensity conditioning.
Finally we thought: “If lymphocytes are so effective at killing the malignancy then perhaps we don’t need to do the transplant procedure at all?”
Perhaps what we need is to treat patients with cancer with conventional treatments. Once they are at the state of minimal disease, and most cancer patients accomplish a stage of minimal residual disease early on following successful initial treatment, we can use donor lymphocytes that are intentionally mismatched because the more mismatched, the more they fight and the more they kill. Intentionally mismatched donor lymphocytes are activated in the laboratory to make them even more aggressive professional killers using IL-2, and can then be given to the patient without stem cell transplantation. In this case however, they will be rejected after approximately a week, unlike in the previous examples where they will stay forever due to the preceding stem cell transplantation. However, while donor lymphocytes don’t last – they kill cancer cells most effectively.
If the patient is truly at the state of minimal residual disease, even a few days may be sufficient to cure them. Again, this is a simple outpatient procedure involving an infusion of activated donor lymphocytes followed by 5 days of outpatient subcutaneous injections of low dose IL-2 in order to continue activating circulating donor lymphocytes. We’ve demonstrated that this can cure patients that are otherwise incurable provided that they are being treated at the stage of minimal residual disease.
Almost every patient with cancer enjoys a stage of minimal residual disease following conventional treatment and at that point the doctor sends the patient away thinking that they are okay. When patients are in remission, that is the best and sometimes the only moment to apply immunotherapy to get rid of invisible residual chemotherapy-resistant cancer cells, particularly cancer stem cells that are a priori resistant to all available anticancer medications. In other words, the key to success is to kill the cancer when you don’t see it. One million cancer cells are the size of a head of a pin, unseen by any of the available technologies, but every cancer begins with a single cell! We need to teach the oncologists and hematologists that the best time for attempting cure by immunotherapy is when they think that there is nothing that needs to be done. Every experienced hematologist or oncologist can easily identify which are the high-risk cases in need of these treatments.
What role do immunotherapies such as these play for late-stage cancer treatments?
For really really late-stage cancer patients the chances are we can’t cure them. If it is just late-stage we can try to do our best with special tricks to minimize the tumor burden and then apply immunotherapy and slow or control disease progression. Cure is rare except if the disease is particularly vulnerable to immunotherapy. The whole point is that we have to avoid it getting to incurable late-stage disease after months of agony with treatment that only induces multidrug resistance.
Interestingly, a new approach known as CAR-T currently seems promising. Developed by an Israeli friend of mine, it is based on a similar principle: using activated patient’s own lymphocytes engineered to express the binding portion of an antibody-like molecule that can target the killer cells to the cancer cells and kill the cancer cell by direct cell-to-cell interaction.
We can now also guide killer cells to the tumor by ‘guided missiles’, using killer cells guided by monoclonal or bispecific antibodies against residual malignant cells. We can identify which antigens are expressed on the malignant cells and then we can choose the proper anticancer antibodies that can bind to special receptors on the killer cells and guide them to residual cancer cells resistant to chemotherapy. We can also prepare anticancer vaccines and use many additional protocols all designed to have an immunotherapy effect against cancer. You have to remember that surgery, chemotherapy and radiation, with all due respect, are not always the final answer.
Your research and practice has been developing for many years now but it is only this year that immunotherapy has been so significantly highlighted at the Annual Meeting of the American Society of Clinical Oncology (ASCO; 29 May–2 June, IL, USA). Why do you think this is?
The problem is that every new idea in medicine takes 10–15 years to get to be recognized. The methods I’ve been talking about were ridiculed before. The other problem is that studies based on cell-mediated immunotherapy are fully personalized – the pharmaceutical agencies which are the major source of funding are less interested in cellular therapy because every patient gets different treatment, not something that brings fast money.
Is it feasible for these therapies to become part of general practice, and if so how long would this take?
The US FDA and European FDA-like agencies hinder progress because they will not let you use a treatment unless you prove that it is really working. To prove, you need to take say 100 patients with one disease, treat 50 and don’t treat the other 50, and show better disease control and improved disease-free survival. This takes a lot of time and costs a lot of money. Putting a new drug to the market costs between US$600 million and $1.2 billion. Again, usually these studies are funded by big pharmaceutical companies because if results are successful they are going to make a lot more money. However, because of the reduced profits associated with personalized medicine, it is very difficult to carry out conclusive studies.
Despite this, everyone understands that personalized medicine is the future because no two cancers are ever the same and no two patients are the same and therefore there is no reason why treatment should be the same for every cancer patient in need. Every treatment plan must take into consideration cancer-specific and patient-specific aspects. Unfortunately, the medical system has not yet found the proper solution for what to do with therapies like this, but now with the recognized anticancer effects of innovative immunotherapy there seems to be some progress in understanding the role of tailor-made personalized medicine.
What are your main focuses looking forward?
Serious investigators and doctors involved in innovative medicine mainly focus on one thing, as usually if you don’t focus you don’t reach anywhere; in my area I am dealing with the top of a pyramid – cellular therapy – but the base is extremely broad because cell-mediated procedures can be used to treat so many different diseases that have nothing in common. In the case of cancer, our focus is immunotherapy by activation of patient’s own immune system and using donor lymphocytes when indicated. The ‘name of the game’ is immunotherapy or targeted therapies based on molecular intervention in the pathways that induce or activate cancer genes, preferably applied at the stage of minimal residual disease. For the time being, in my opinion, that is the only way to make progress and cure cancer.
Shimon Slavin is the Medical and Scientific Director of the International Center for Cell Therapy & Cancer Immunotherapy, where he carries out both basic clinical research and patient trials investigating new ways of promoting immune responses to disease in patients. He currently has in excess of 500 research articles published in top peer-reviewed journals. Read more about Professor Slavin’s work here.
Disclaimer: The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Oncology Central or Future Science Group