Alemtuzumab-induced autoimmunity: getting closer to answers

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.

SAN DIEGO – The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis, but there’s a catch — the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

“This is an efficacious treatment in multiple sclerosis” that can slow the rate of brain atrophy over the long-term, Alasdair Coles, MD, said at ACTRIMS Forum 2018, held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “But 1 or 2 years after each cycle of alemtuzumab [Lemtrada], patients are at very high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some very troubling and potentially highly threatening complications at lower frequency.”

Subsequent autoimmune thyroid disease can affect up to 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About 1 in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies (10%).

“People ask: ‘Why doesn’t MS come back as part of this generic mechanism?’ and I don’t know the answer to that,” Dr. Coles said.

In the United States, alemtuzumab is indicated for treatment of relapsing multiple sclerosis in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the U.K.,” said Dr. Coles, a professor in the department of clinical neurosciences at the University of Cambridge (England).

“Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering the prospects for different proposed mechanisms

Dr. Coles shared some encouraging news at ACTRIMS Forum 2018. His team and other researchers are getting closer to understanding the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Published reports in the literature from others suggest faulty immune B cells could be the culprit, pointing to a similar reconstitution of B cells after bone marrow transplantation. However, he said, “There is no difference in this reconstitution pattern between those who do and don’t get autoimmunity. So we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.”

Other investigators have pointed to possible depletion of a key immune regulatory cell associated with alemtuzumab, such as alterations in CD52-positive T cells that cause depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “I’m not going to describe why we don’t believe any of this,” Dr. Coles said, but added, “We cannot replicate the data in type 1 diabetes or MS about the depletion of T cells.”

Along with his colleague Joanne Jones, PhD, a clinical fellow in the same department at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We don’t know if alemtuzumab is having a direct impact on the thymus or if it’s an indirect effect though a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast to B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, Dr. Coles explained.

“These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and have impaired thymic function compared to those who don’t.”

As the theory goes, the limited clonal repertoire leads to expansion of the T cells, preferentially expanding autoreactive T cells, leading to B-cell- and antibody-mediated autoimmunity.

The bigger picture

The autoimmune phenomenon is not unique to alemtuzumab or multiple sclerosis. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said.  A similar effect was seen years ago when very lymphopenic HIV patients were given antiviral therapy, he added, affecting about 10% of treated patients. About 10% of bone marrow transplant patients may experience similar autoimmune concerns.

“What we do think is true is we’ve tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”

A ‘tantalizing prospect’

“It’s a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. One promising lead, he added, is “we also looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum IL-21 is greater in those who subsequently develop autoimmune disease. This suggests some individuals are prone to develop autoimmune disease, and could be identified potentially prior to treatment with alemtuzumab.”

More work is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.”

A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, leading to a more diverse immune repertoire, Dr. Coles said. “The obvious corollary of this is if we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”

Dr. Coles disclosed that he receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.