Cancer Treatment Today » Immunology

Antibodies to inflixumab

M Levin, MD — Thu, 26 Dec 2013 16:17:57 +0000

Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). Lower drug levels can mean less effect ont eh disease. It is clinically useful to be able to assess and predict diminishing response. A recent meta-analysis concluded that the presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. However, most studies were flawed in that published studies on this topic lack uniform reporting of outcomes and high risk of bias was present in all the included studies.

Similar conclusions are reached by reviews that look at this question and are likewise limited in the same way. For example, a recent paper outlines why antibodies to infliximab (ATI) cannot be used as a surrogate marker for immunogenicity,
or to predict clinical outcome or safety. This is because up to half of patients still need dose adjustment for recurrent symptoms and 20% of patients lose response, even when treatment is optimised to avoid ATI through scheduled maintenance therapy or concomitant immunomodulators. The effects of ATI is, therefore, diluted statistically in these studies.

Thus far many questions persist about how useful ATI testing can be. Measurement of serum antibodies to infliximab has not received clearance by the FDA andthere is not sufficient peer-reviewed scientific literature that demonstrates that the procedure is effective.

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Immunoglobulin for Gullain-Barre Syndrome

M Levin, MD — Sun, 14 Jul 2013 22:05:45 +0000

Guillain-Barr syndrome is a disorder in which the body’s immune system attacks part of the peripheral nervous system. The onset can be very rapid or take few days to few weeks. Symptoms are weakness or tingling sensations in the legs. Sometimes, the weakness and abnormal sensations spread to the arms and upper body and progress to paralysis. There is no known cure for Guillain-Barr syndrome, but therapies can lessen the severity of the illness and accelerate the recovery in most patients. Often life support is required until the patient begins to recover. As such, any treatment that can speed recovery is valuable. Currently, plasmapheresis and high-dose immunoglobulin therapy are most often used.

Both plasma exchange (PE) therapy and intravenous immune globulin (IVIG) have proven effective for Guillain-Barr syndrome (GBS). They are both thought todecrease autoantibody production and increase removal of immune complexes. Both have been shown to shorten recovery time by as much as 50%. IVIG is easier to administer and has fewer complications than PE. and is usually the initial treatment.

Randomized trials in severe disease show that IVIG started within 4 weeks from onset hastens recovery as much as plasma exchange. Combination therapy of both, does not improve outcomes or shortened illness duration over one or the other.

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Treatment of Langherhan’s Hystiocytosis

M Levin, MD — Fri, 24 Aug 2012 17:14:26 +0000

Histiocytosis is a rare disease that involves cells called hystiocytes. The disease can range from limited involvement that spontaneously goes away to progressive multiorgan involvement that can be chronic and debilitating. In some cases, the disease can be life-threatening. It is approximated that histiocytosis affects 1 in 200,000 children born each year in the United States. The disease us rare and not much is known securely about how to treat it. Because of its rarity, prospective studies are not possible.

In 2009, a guideline was published by the Hystiocytosis Society. It recommends an initial 6-week course of therapy with vinblastine and prednisone for all patients regardless of risk organ involvement. It is also recommended that all patients who have complete disease resolution
after 6-12 weeks of initial therapy continue with maintenance therapy. Maintenance therapy consists of pulses of vinblastine and prednisone every 3 weeks and daily continuous 6-mercaptopurine (6MP) for total treatment duration of 12 months. Currently, there is insufficient evidence to support an optimal course of treatment for use with patients suffering from severe progressive disease who do not respond to standard therapy. Recently, promising results have been reported for patients treated with a combined regimen of 2-chlorodeoxyadenosine (2-CdA, Cladribin, Leustatin) and cytarabine (Ara-C) (12); as well as stem cell transplantation after reduced intensity conditioning regimen (RIC-SCT). However, the results generated by both reports are based on limited observations and must be validated by the prospective clinical trials, which is, as we said, logistically very difficult to put together.

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BMS-936558 (MDX-1106)

M Levin, MD — Fri, 24 Aug 2012 13:32:54 +0000

BMS-936558 is an antibody against PD-1, a protein involved in repressing the immune system. It activates the immune system and enables it to fight tumors. A well established approved drug, Yervoy blocks CTLA-4, another inhibitory protein expressed on immune cells and Yervoy and BMS-936558 belong to the same class of drugs. Both generate an anti-cancer immune response.

This very promising agent is in several trials for various diagnoses. For example, for renal cancer there is the Phase II trial of BMS-936558 (MDX-1106) in Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Tx and CA209-009 biolarker trial. There are also combination studies with various malignancies. It is a promising agent but still investigational.

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IMC-A12

M Levin, MD — Mon, 20 Aug 2012 20:07:45 +0000

It has gradually become clear that insight is involved in the cancer growth and regulation. Insulin Growth Factor Receptor(IGFR) is important in this process. IGF-IR blockaded by IMC-A12 results in rapid and profound growth inhibition of cancers of the breast, lung, colon, and pancreas, and many other cancers. Although promising single-agent activity has been observed, the most impressive effects of targeting the IGF-IR with IMC-A12 have been noted when this agent was combined with cytotoxic agents or other targeted therapeutics. So far, only a few preliminary human studies had been published, including in Ewing sarcoma. This drug may also have applications in auto-immune disorders. It remains an experimental drug.

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Anti-PD-1 Human Monoclonal Antibody MDX-1106

M Levin, MD — Mon, 20 Aug 2012 19:59:10 +0000

A now well established approach to cancer immunotherapy is using antibodies that are directed against substance (antigen) on a cancer cell surface. A monoclonal antibody is a molecule that attaches to the cancer cell and causes changes within it or in immune cells around it, or it can carry a toxin or a radioactive material to the cancer cell. A fully human monoclonal antibody directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) it activates the immune T cells and induces cell-mediated immune responses against tumor. These antibodies can restore the immune efforts to kill cancer cells or to inhibit their growth. First use in humans was published by Berger et al in 2008 and showed that a single administration is safe and well tolerated in patients with advanced hematologic malignancies. A more recent report in 2012 in the prestigious New England Journal of Medicine in 296 patients found cumulative response rates (all doses) of 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). On the other hand, Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. Ongoing studies should bring more clarity to how this agent can contribute to treating cancer.

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NK cells in medicine – pro

M Levin, MD — Wed, 20 Jun 2012 19:37:34 +0000

Natural killer (NK) cells are major actors of innate immune responses against viruses, bacteria, parasites, and other mediators of pathology such as malignant transformation. These cells are also directly implicated in the link between innate and adaptive immunity, shaping T-cell responses. It is now obvious that manipulation of this lymphocyte subset could be the basis of new therapeutic approaches for cancer and/or pathogen-driven pathology. There is an interest in these cells in reproductive medicine, which is not a focus of our discussion.

There is some older evidence that loss of NK activity as an indicator of relapse in acute leukemia. They concluded that there was a marked reduction in NK activity in patients with active leukemia when compared with healthy controls, and that NK activity substantially
improved in complete remission. What this means for clinical medicine is not clear. Patients with CD20+ follicular lymphoma fared better when treated with the humanized anti-CD20 monoclonal antibody rituximab if their FcγRIIIa gene had a polymorphism that resulted in higher affinity for rituximab and enhanced ADCC activity in vitro; however, therapeutic attemtps to use this information have failed.

The NK is currently in the stage of gathering information and conceptualizing it into a set of insights that can then be studied. It is not ready for routine clinical use.

REFERENCES:
Dearden CE, Johnson R, Pettengell R, Devereux S, Cwynarski K, Whittaker S, McMillan A Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma).Br J Haematol. 2011 May;153(4):451-85.

Caligiuri MA. Human natural killer cells.Blood. 2008 Aug 1;112(3):461-9.

Khan KD, Emmanouilides C, Benson DM Jr., et al. A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin’s lymphoma. Clin Cancer Res 2006;12:7046-7053.

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NK cells in medicine

M Levin, MD — Wed, 20 Jun 2012 18:39:56 +0000

Natural killer (NK) cells, a type of T lymphocyte cell, are major actors of the body’s immune responses against viruses, bacteria, parasites, and other mediators of pathology such as malignant transformation. These cells are also directly implicated in the link between by preexistent body’s own and adaptive, newly developed immunity, shaping T-cell responses. It is now obvious that manipulation of this lymphocyte subset could be the basis of new therapeutic approaches for cancer and/or pathogen-driven pathology. There is an interest in these cells in reproductive medicine, which is not a focus of our discussion.

There is some older evidence that loss of NK activity as an indicator of relapse in acute leukemia. These studies concluded that there was a marked reduction in NK activity in patients with relapsed leukemia when compared with healthy controls, and that NK activity substantially improved in complete remission. What this means for clinical medicine is not clear. Patients with CD20+ follicular lymphoma fared better when treated with the humanized anti-CD20 monoclonal antibody rituximab if their NK cell driven responses worked better than ones who did not; however, therapeutic attempts to use this information to develop novel approaches have failed.

The NK field is currently in the stage still of gathering information and conceptualizing it into a set of insights that can then be refined and applied. It is not ready for routine clinical use.

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Interferon for hypereosinophilic syndrome

M Levin, MD — Wed, 20 Jun 2012 22:29:04 +0000

Chronic myeloproliferative disorders (CMPD) are classified according to the WHO classification of 2001 as polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia, and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome, all to be delineated as different from another member of the group, BCR/ABL-positive chronic myeloid leukemia (CML). This article addresses specifically the rare hypereosinophilic syndrome.

Hypereosinophilic syndromes (HES) and systemic mastocytosis (SMCD) are a group of disorders with clinical symptoms from local and remote effects of excessive proliferation of eosinophils, a type of a blood cell and mast cells, respectively. Interferon alpha (IFN-alpha), alone or in combination with other medications, can be a useful, and at times life-saving, treatment for patients with HES. Receptors for IFN-alpha are present on eosinophils, and clinical benefits are due to its effect on eosinophil growth, movement, activation, and survival. These effects are likely mediated through multiple pathways, not all of which are known or understood. A number of case reports showed that IFN-alpha has been life-saving for patients with intractable HES that were resistant to prednisone, hydroxyurea, and other agents used for myeloproliferative syndromes. There are reports of its combined use with hydroxyurea and prednisone. There are also reports of the use of peg-interferon.

Unfortunately, HES is rare and prospective trials are not reasonable to expect. I did find that the PDQ from the National Cancer Institute recommended interferon for this disease.

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