Clinical testing begins
A drug for cancer and transplantation medicine
Once the initial laboratory testing had been completed and some safety studies had been conducted with Campath-1M in primates, Waldmann and his team were ready to launch their first pilot study in humans. The aim of the trial, conducted in 1982, was to check the antibody's safety before launching larger studies to see if could improve the safety of BMTs.
The first patient to be given Campath-1M was FB, a man suffering from end-stage non-Hodgkin's lymphoma, a type of blood cancer. He was a patient of David Swirsky and Frank Hayhoe in the Haematology Department next door to Waldmann's laboratory. Disappointingly, the antibody cleared FB's tumour cells from his blood only temporarily and the cells bounced back 24 hours after each dose. Such results were, nonetheless, fairly representative of what other researchers were then experiencing in the use of monoclonal antibodies in treating cancer patients elsewhere. Results from the trial were published in G. Hale et al., 'Effects of monoclonal anti-lymphocyte antibodies in vivo in monkeys and humans', Molecular Biology & Medicine, 1 (1983), 321-4. Click here to see more data collected from the pilot study which was kept in Geoff Hale's laboratory notebook.
FB died as a result of his underlying disease shortly after completing his course of Campath-1M. However, he had tolerated the treatment well and experienced no toxic effects with repeated doses of the monoclonal antibody. This encouraged Waldmann and his group to go on to test Campath-1M in other patients. The second person treated was a man called AP. He again initially responded well to the treatment, but died from his underlying disease when it ended.
Soon after Campath-1M was tested in AP, it was given to a woman suffering from leukaemia. While it had little impact on her leukaemia, it proved effective in removing her T-cells and activating complement. The drug also proved well tolerated by the patient.
Based on the pilot testing, Waldmann and his team believed Campath-1M merited clinical investigation for BMTs. They, however, had little precedent for carrying out such work, so were trepidatious about going forward. What they were most concerned about was whether the drug would destroy the beneficial blood stem cells contained in bone marrow alongside killing the T-cells that caused GVHD. The challenge they faced was finding an appropriate patient for such a test.
The first patient chosen for the Campath-1M BMT study was a woman suffering from severe aplastic anaemia, a condition in which the bone marrow produces insufficient new cells to replenish blood cells. The woman faced a strong possibility of dying if not given a BMT. Unable to find a suitable matching sibling donor, she was to receive bone marrow from an unrelated but genetically matched donor. Receiving bone marrow from an unrelated donor was still highly experimental and carried a high risk of GVHD.
This is a photo of Shimon Slavin who opened the first BMT unit in Israel in 1978. Credit:Pnina Evental.
In 1982, Waldmann, working with Jill Hows and Ted Gordon Smith during a clinical training stint at the Hammersmith Hospital, gave Campath 1-M to the aplastic anaemia patient. To their delight, the woman's bone marrow appeared to recover after treatment. Subsequent analysis of her marrow, however, suggested that her blood system had been reconstituted by own stem cells rather than by her donor's cells. This was surprising because, prior to treatment with Campath-1M, her body had been unable to make any of its own bone marrow cells. While good news for the patient, the findings made the Hammersmith clinicians nervous that Campath-1M could be having an impact on stem cells and they decided to abandon any further testing of the drug. In due course, however, the experience gained from treating the Hammersmith patient led to further studies applying Campath antibodies in aplastic anaemia.
With the trial halted at Hammersmith, another route was sought for testing Campath-1M. This was to come about through a chance meeting at a transplant conference in Squaw Valley, California, between Steve Cobbold, from Waldmann's team, and Shimon Slavin, a clinician based at Haddasah Hospital in Jerusalem. Slavin had been performing experimental BMTs in patients with leukaemia for some years and had first learned about monoclonal antibodies on attending a talk given by Milstein in Jerusalem.
Waldmann and Slavin launched a series of tests to evaluate Campath-1M in a small cohort of eleven leukemia patients whose prognosis was poor. The trial involved mixing Campath-1M with bone marrow taken from matched donors and then infusing the mixture into patients. The proceedure allowed for the destruction of T-cells in the bone marrow before being given to a recipient so as to prevent GVHD. What the trial showed was that Campath-1M was an effective treatment for the prevention of GVHD in BMTs, reducing its incidence from 40 to 10 per cent in patients. This was achieved without any post-transplant prophylaxis. Some of the patients continue to be alive and well today, more than 30 years on.
Despite the promising results for GVHD, two out of the eleven patients treated at Hadassah Hospital experienced a rejection of their bone marrow grafts during treatment and could not be rescued with a second or third graft. Such a rejection rate was unacceptable. Waldmann and his team hypothesised the complication might stem from a residual of the patient's T-cells being left by the conventional treatment they were given to destroy such cells in an effort to condition their body to accept tissue from a donor. Based on this reasoning, they wondered whether they might resolve the problem by administering Campath-1M directly into patients rather than mixing it with the bone marrow prior to infusion. Taking such a step, however, posed a significant risk. The team, therefore, decided to take a break from clinical testing and return to the laboratory to investigate further. It was important to establish which T-cell subsets were responsible for rejecting marrow and then determine what monoclonal antibody could be developed to combat the problem. Their thinking was published in S.P.Cobbold, G.Martin, S.Qin and H.Waldmann, 'Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance', Nature, 323 (11Sept 1986), 164-66.
Up to this moment in time, the type of monoclonal antibody Waldmann's group had been testing was an IgM antibody. This is a class of antibody produced by the immune system immediately after exposure to a foreign invader. Such antibodies exist only temporarily and usually disappear from the body within two to three weeks. They are then replaced by IgG antibodies, which, lasting a life-time, provide long-term immunity against a disease.
Based on experiments conducted by Steve Cobbold, which indicated that IgG monoclonal antibodies could help prevent both graft rejection and GVHD in mice given BMTs, Waldmann and his researchers turned their efforts to developing an IgG antibody that could be deployed in humans. The work was painstaking and time-consuming. It necessitated the study of the genetic structure of monoclonal antibodies and the screening of 20 million different monoclonal antibody clones, a heroic task undertaken by Geoff Hale. In 1985, a suitable IgG antibody suitable was eventually identified for clinical testing. It was labelled Campath-1G.
The first person chosen for testing Campath-1G was a man suffering from chronic lymphocytic leukaemia (CLL), a cancer of white blood cells (leucocytes). CLL affects a particular leucocyte - the lymphocyte - which is responsible for fighting infection. These lymphocytes undergo abnormal growth in the bone marrow and the lymph system, which causes swelling in the lymph nodes as well as fatigue, anaemia and persistent infections as a result of global immunosuppression. The disease is one of the most common types of leukaemia and usually occurs in older patients.
The patient selected for Campath-1G treatment was a man being cared for by the clinicians Martin Dyer and Frank Hayhoe in the Haematology Department at Addenbrooke's Hospital next door to Waldmann's laboratory. He was not only rapidly getting worse, but had failed to respond to chemotherapy. Promisingly, however, his tumour cells appeared sensitive to Campath-1H when tested in a test tube.
This photo, taken in the 1980s, shows a stack of culture flasks containing hybridoma cells generating Campath used in the early clinical trials conducted among patients receiving BMTs. Credit: Geoff Hale.
The man was given his first dose of Campath-1G in 1987. His response to the antibody went well beyond what Waldmann and Hale described as their 'most optimistic expectations'. Ten days after treatment, he had gone into what seemed to be complete remission, with his tumour cells completely cleared from his blood and bone marrow. The result was astonishing. Waldmann and Hale comment, 'Many sincere prayers had been offered for this man and it did cross our minds that divine intervention might have overruled our efforts!'
Just a few days later, however, the man's cerebrospinal fluid was found to contain some large tumour cells. In a bid to save him, the team infused Campath-1G directly into his cerebrospinal fluid. To their disappointment, while the antibody appeared to be well tolerated by the patient, it had little impact on his tumour cells. A few weeks later the man died, having failed to respond to other therapies. His death was attributed to his underlying disease.
Although Campath-1G failed to rescue the patient, the results gathered from his treatment encouraged Waldmann and his colleagues to believe the drug could be effective in others. To this end, they decided to treat a second patient. The candidate was a woman suffering from CLL, who had been treated with two earlier versions of Campath. Helped temporarily by Campath-1M, her disease had been held in check with chemotherapy for 2 years, but she was now deteriorating rapidly. Campath-1G again led to a dramatic improvement in the woman's condition, helping to clear the majority of tumour cells from her blood and, to a lesser extent, from her bone marrow. A few weeks after completing treatment, however, tumour cells reappeared in her blood, albeit in a smaller number than before.
While the first two patients treated with Campath-1G failed to survive in the longer term, the evidence collected from these two cases indicated the drug to be potentially useful for reducing GHVD associated with BMT. Many more patients would nonetheless need to be tested before any conclusions could be reached. Undertaking larger trials however, was not going to be easy given the small number of patients receiving BMTs at the time. To overcome the problem, Waldmann and his team set up a Campath Users Network with clinicians working in transplant centres worldwide to undertake different types of testing with the drug. The establishment of the Network was helped by the fact that clinicians performing BMTs liked participating in pilot investigations of the kind needed for testing Campath. Each clinician was to receive supplies of Campath in exchange for reporting back their results from testing, so that they could to be fed into a computer in Waldmann's laboratory for analysis.
While the international collaborative study as was pursued by the Campath Users Network is common today, it was highly unusual for the 1980s. Those involved in the study included clinicians from several transplant centres based in England, as well as Israel, Germany, the Netherlands and South Africa. Over the ensuing years, the number of studies conducted with Campath for BMT would continue to grow, such that by 2000 the Campath Users Group had collected data on 4,264 patients in a central registry. This evidence indicated Campath-1G, and a later humanised form, known as Campath-1H, to be an effective drug for preventing GVHD and graft rejection. Campath would continue to be studied for BMTs over the following years. Between 2003 and 2004, for example, Campath was used in over 1500 transplants in the USA.
Pictured here is Roy Calne, a British surgeon who in 1968 performed the first European liver transplantation operation and in 1987 the world's heart and lung transplants. He was also instrumental in the adoption of the immunosuppressive drug, cyclosporin, for improving the survival chances of patients undergoing organ transplants. Credit: Cambridge University.
By the 1990s, Waldmann had begun working closely with Roy Calne, a British surgeon based at Addenbrooke's Hospital, with whom he had a strong collegial friendship. Calne had a long-standing interest in immunosuppressive drugs, having shown the power of the drug Cyclosporin to prevent organ rejection in patients in 1978. Since that time he had investigated a number of other immunosuppressive agents for this purpose.The use of such drugs helped transform the management of organ transplants and radically improved the length of survival of patients undergoing the operation.
As early as 1985 Calne undertook some preliminary investigations of Campath-1M as an immunosuppressive agent for transplant patients, but did not pursue testing the drug any further because he was wary of its potential toxicity. By the late 1990s, however, he had reconsidered his position based on research reported from Wisconsin, USA, which showed that another monoclonal antibody that depleted T-cells was effective in prolonging the survival of monkeys receiving organ transplants. His thinking was reinforced by the fact that by this time the original Campath-1M monoclonal antibody had been re-egineered to be more human-like, labelled Campath-1H, which was much safer and had less toxicity than its predecessor.
What Calne and Waldmann wondered was whether Campath-1H would not only help in the prevention of organ rejection in the immediate aftermath of a transplant, but might help reduce the amount of immunosuppressive drugs patients need to take thereafter. This was a critical issue. While immunosuppressive drugs had greatly improved the management of organ transplants, they had not proven not a panacea. Patients noty only need to stay on such drugs for life, which necessitates swallowing many tablets at regular times every day, but the drugs can also cause severe or life-threatening side effects, such as infection, cancer, renal damage, bone necrosis, diabetes hypertension and hyperlipidemia. Such drugs can also cause unpleasant side effects, such as increased hair growth and weight gain. The complications associated with immunosupressant drugs often lead to patients abandoning treatment. This can have disasterous consequences, because cessation of medication can often result in organ rejection, which if not caught in time can lead to the loss of the organ.
Calne and Waldmann were eager to find a means of improving the management of organ transplants which would enable patients to move away from the use of immunosuppressive drugs. The goal was to find a means to activate a recipient's immune system to become tolerant of their donor's tissue. Their optimism in this area was fueled by Calne's observation in the late 1960s that pigs which received liver transplants, while initially experiencing symptoms of rejection went on to accept the grafted organ spontaneously soon after their transplant without any immunosuppressive intervention. Calne and Waldmann reasoned that Campath-1H could provide the means to enforce immunosuppression at a minimal level that would permit graft acceptance. They hypothesized that it might be possible to use Campath-1H as an induction treatment, followed by a low-maintenance immunosuppression regimen. By depleting a patient's T-cells, Campath-1H could encourage a patient's immune system to reprogramme itself so as to tolerate a grafted donor organ.
In 1997, Calne, together with Peter Friend and Waldmann's team, launched a small non-randomized, open-label single-centre clinical trial with 31 kidney transplant patients. During the trial the patients were to receive Campath-1H intravenously at a dose of 20mg on day O and 1 after the transplant, and then cyclosporine 72 hours after the transplant. Results from the study indicated not only that Campath-1H was safe, but that patients experienced high graft survival. Moreover, the incidence of rejection was low as were rates of infection. Encouragingly, the trial patients no longer needed steroids and only low doses of immunosuppressive drugs. To see the research see R. Calne, P. J. Friend, S. Moffatt, et al., 'Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients', Lancet, 351 (1998), 1701-2 and R. Calne, S. D. Moffatt, 'Campath 1H allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients', Transplantation, 68 (1999), 1613-6.
The first study would be followed by several others. An analysis of these different trials, reported in 2011, indicated that while Campath-1H did not allow for the total elimination of immunosuppressive agents, it allowed for a reduction in the doses of the drugs used, thereby helping to reduce the side effects of such drugs and cut down on the costs associated with such therapy. What the research showed was that Campath-1H was better tolerated and gave better results when given at low doses before transplant rather than as a treatment for acute rejection. For a discussion of the results see R. Calne, C.J.E. Watson, 'Some observations on prope tolerance', Current Opinion in Organ Transplantation, 16 (2011), 353-8.
Painting of a transplant operation by Roy Y. Calne. The painting captures the compassion of the surgeon and the human skill and compassion of the Intensive Care nurse. Commissioned by Goram Klintmalm in Dallas.