Boosting the patient’s immune system to battle cancer

Donor lymphocyte infusion – Extract “killer” cells from a mismatched donor, inject them into a patient at the stage of minimal residual disease, and they can kill the remaining cancer.

These kinds of treatments have already been successfully used on thousands of patients worldwide. The first and one of the most astounding cases where DLI was used to treat cancer in a human patient was a two-and-a-half-year-old toddler with leukemia who had gone through all types of conventional therapy, including radiation four times the lethal dose and bombardment with some of the most poisonous drugs available, including a lethal dose of whole body irradiation. He managed to survive the treatment, but the cancer returned with a tumor mass in his blood and marrow with visible tumor masses on his forehead and next to his trachea, obstructing his airway. As a last resort he was given an injection of blood from his sister once a week for six weeks. The tumor masses disappeared and the boy was completely cured. He is alive today, more than 20 years later. Since then, many patients, most with hematological malignancies and some with metastatic solid tumors, were successfully treated by Slavin using either short-lived donor lymphocytes or long-lived donor lymphocytes following tolerance induction by stem-cell transplantation.

Choose your weapons carefully

Q: When and why did you become interested in immune-therapy? And when did you realize that it could indeed cure cancer?
A: I was interested in immunotherapy because I was disappointed from the results of treatment of patients’ hematological malignancies and metastatic solid tumors with conventional anticancer modalities, which cause a lot of side effects on the one hand, and very little benefit on the other. Being involved transplantation immunobiology it was clear to me that once the immune system can recognize a tissue as “non self” rejection is imminent, regardless of the volume of the tissue. This working hypothesis gave me an idea that if I can use an allogeneic immune system that will recognize cancer cells as “non self” immune reaction against such undesirable tissue could be most effective, not leaving a single cell alive, exactly as is the case when an allograft is placed with no post grafting immunosuppressive treatment.

Q: Immune-therapy for many years has been mostly bad-mouthed, owing to fairly disappointing results. Why do you feel that, despite all the failures, immune-therapy holds undiscovered promise?
A: It is true that wishful thinking based on preclinical animal models resulted in great hope in immunotherapy, while clinical experience was mostly disappointing. However, in view the strong rationale and successful outcome in patients with hematological malignancies it became clear to me that immunotherapy has a lot of potential once we understand the rules of the game. Most efforts with immunotherapy until my time were based on the use of patients own immune system cells, trying to divert them to induce reactivity against patient’s own cancer cells. Unfortunately, this procedure seemed insufficient because if patients own immune system cells could recognize the first cancer cell as being different from normal “self,” a potential enemy, that patient will not have cancer to start with. The fact was that the first cancer cell and daughter cells then after, evaded the immune system successfully, and in addition probably down regulated the immune system and even induced tolerance or unresponsiveness to the emerging cancer cells. Taken together, our working hypothesis suggested that instead of relying on patient lymphocytes, it would be much easier to break the tolerance that exists between patient’s immune system and his own cancer cells using allogeneic lymphocytes, which are likely to be alloreactive. That simple concept suggested to me that perhaps the better way to use anticancer effector cells therapeutically would be to use allogeneic immune system cells, especially if such cells can circulate permanently in the host, following induction of transplantation tolerance by prior engraftment of donor stem cells. Durable engraftment of donor lymphocytes will allow ample of time to eliminate cancer cells recognized as “non-self.”

Q: Do you think it is possible to use animal lymphocytes to fight human cancer instead of needing a human donor?
A: Unfortunately animal lymphocytes do not fight well against human target cells and therefore it is unlikely that such cells can be used for immunotherapy except perhaps if we use primates that are closest to humans.

It is very difficult, for example, to induce graft-vs.-host disease with human lymphocytes against mice, whereas the mirror image experiment cannot be done…

Q: If a cancer patient is interested in receiving immune-therapy, is it available to anyone, or is it only performed at certain centers?
A: Immunotherapy is considered experimental treatment and therefore available only in centers of excellence that are involved with experimental medicine. Since most immunotherapy procedures are not considered evidence-based medicine, many major centers are not applying immunotherapy as a standard of care and unless believers familiar with basic immunology involved with patient’s care will be involved in providing care using methods based on innovative immunotherapy for patients in need under their care, in full collaboration with basic scientists and cell biologists, no progress is to be anticipated.

Q: What, in your view, are the major bottlenecks that need to be passed technologically to make immune-therapy the first choice for treatment of cancer?
A: In order to make sure the experts in the field will accept immunotherapy as a legitimate treatment, let alone treatment of choice for patients with full resistance to conventional anticancer modalities, several reproducible prospective randomized clinical trials must be accomplished. To do such studies takes a lot of collaborative effort and funding and many years of observation while closely observing recruited patients on a long tern basis. Obviously, no company is likely to support treatment program based on Mother Nature tool – the lymphocytes. Also, referring oncologists will not refer patients that are suitable for immunotherapy because they do not believe in methods that are not proven effective. Yet, there is no way to prove a method is effective unless oncologists will cooperate and send patients for clinical trials. This is catch 22, which explains why there is such a slow progress in the field. Another important factor is due to the fact that pharmaceutical companies that usually are behind large and expensive clinical trials are not particularly interested in using mother nature tool – the lymphocyte – because they rather prefer to support standard off-the-shelf anticancer agents. Unfortunately such studies are most difficult to produce:
 immunotherapy is one form of personalized treatment method, whereas the name of the game likely to draw the attention and financial support of the pharmaceutical industry is to develop standard medications suitable for all patients with the same disease category. 

Q: The idea of DLI curing cancer seems almost too good to be true, but where is the catch? What are the major drawbacks?
A: Donor lymphocyte infusions (DLI) seem to be effective for some patients, particularly for the treatment of diseases such as chronic myelogenous leukemia and some others. DLI may not be effective against rapidly developing relapsing malignancies and also against bulky disease, and the reasons could be some of the following:

1. When DLI is done between MHC compatible donors and recipients the anticancer effect of such immunotherapy may not be optimal due to the intentional compatibility between the effecter cells and their targets.

2. Following allogeneic stem cell transplantation GVHD must be prevented by immunosuppressive treatment for several months and any treatment that prevents GVHD or treatment that is used to treat GVHD also neutralizes the potential beneficial effects of the T-cells included in the DLI, both being mediated by donor T-cells.

3. Since the beneficial effects of DLI are directly related to alloreactivity of donor cells against host alloantigens, benefits of DLI are frequently if not nearly always associated with acute and chronic GVHD which can be hazardous or even lethal. Consequently, once treatment is applied, the benefits of DLI may be minimal and time consuming, while the risk of GVHD will be ongoing progressively.
4. Not every cancer cell is a good antigen-presenting cell and therefore, non-immunogenic cancer cells may not stimulate donor T-cells sufficiently well.

5. For DLI to be effective donor effecter cells must recognize cancer cells through antigen presentation and some cancer cells may not express antigenic determinants in association with class II which is the way helper T-cells recognize their relevant stimulatory peptide.