Immunotherapy can take 3 years to desensitize to allergens

Sublingual immunotherapyImmunotherapy can induce tolerance for allergens, but what is a realistic time frame? A study recently published in JAMA demonstrates that 3 years of sublingual desensitizing treatment is effective, but 2 years is no different than placebo. This research helps practitioners working in the larger context of immune plasticity, and patients, to consider pragmatic parameters for case management. The authors note:

“Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.”

But since reducing the inconvenience and expense of treatment is always desirable, the they set out to…

“…assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.”

3 years of immunotherapy effective, 2 years comparable to placebo

In a randomized double-blind, placebo-controlled, 3–parallel-group study of adult patients with moderate to allergic rhinitis that was severe enough to interfere with normal daily activities and sleep), thirty-six subjects received 2 years of sublingual immunotherapy (SLIT; daily tablets containing 15 µg of a major allergen and monthly placebo injections), another 36 received subcutaneous immunotherapy (SCIT; monthly injections containing 20 µg of the allergen and daily placebo tablets); and 34 received double placebo. The nasal allergen challenge was performed before and at 1 and 2 years during treatment; and at 3 years, which was1 year after treatment concluded. Their data make clear that, while the effectiveness of 3 years of treatment is well established, 2 years of treatment did essentially nothing.

“Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score [total nasal symptom score] for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).”

In other words, there were no significant differences between the placebo group and the treatment groups, or between the two treatment groups, despite the finding that SCIT appeared to be more effective than SLIT at reducing TNSS after 1 year.

Medscape Family Medicine quotes an editorial by Linda S. Cox, MD:

“…the cumulative costs of symptomatic drug treatment for perennial or seasonal allergic rhinitis can be significant over time,” because it is a chronic condition. Therefore, any analysis of allergen-specific immunotherapy must take into account its potential for long-term disease modification. However, she warns, any cost-benefit assessment of allergen-specific immunotherapy must include “the duration of treatment required for optimal long-term efficacy.” The time commitment requirement may be an important factor in patients’ decisions to initiate therapy.” Therefore, it is important to clarify the optimum duration of treatment. The findings of this study suggest that “2 years is not sufficient for SLIT treatment to induce long-term clinical efficacy.”

Clinical note

This study leaves open the question as to whether adjunctive forms of immunomodulation can accelerate sustained benefit or improve outcomes in other ways, but it does offer one reference by which clinicians and patients can appreciate the dynamic and time frame of therapies addressing immune and neuroplasticity.

The authors conclude:

“Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.”

Immunepheresis: a vastly under-utilized cancer therapy that deserves far more attention

It has long been known that tumor cells defy destruction by immune cells by producing cytokine ‘decoys’ called soluble TNF-α (tumor necrosis factor-alpha) receptors. TNF-α is a ‘guidance system’ for the immune attack that seeks its receptors on malignant cell membranes. The soluble receptors (TNF-R) shed by tumor cells into their local environment divert the TNF-α by binding them. A paper published sixteen years ago in the British Journal of Cancer documents their presence in breast cancer:

“The expression of tumour necrosis factor alpha (TNF-alpha) and its two distinct receptors, TNF-R p55 and TNF-R p75 [soluble receptors], was…was not detectable in normal breast tissue or in non-malignant breast tissue adjacent to the tumours.”

It was a different story for the tumors examined:

“TNF-R p55 was expressed by a population of stromal cells in all the tumours examined, and a varying proportion of neoplastic cells in 75% of these tissues. TNF-R p75 was detected in about 70% of the tumours…”

It has been known for just as long that the presence of soluble tumour necrosis factor receptors can predict the outcome for a cancer patient. A paper published in The Lancet around the same time references a number of earlier studies on the topic.

A couple years later a similar observation was reported in a paper published in the European Journal of Cancer for melanoma. The authors note:

“It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer.”

They proceed to describe increased concentrations of soluble TNF receptors in association with adhesion molecules that also participate in tumor development:

“We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-Rl levels were detected only in patients with metastatic melanoma compared with normal controls, whereas sTNF-R2 levels were increased both in primary and metastatic melanoma…A correlation between sTNF-Rs and sICAM-1 concentrations in patients’ sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.”

These observations were soon followed by research that further confirmed the blockade of anti-tumor immune mechanisms by soluble TNF receptors. A paper published in the journal Immunology also mentions early trials of ultrapheresis (another term for immunepheresis = filtering from the blood of soluble TNF receptor ‘decoys’):

Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour immunity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis, an experimental extracorporeal treatment for cancer.”

The authors designed their study to resolve definitive proof that sTNFRI specifically blocks immune efforts at tumor removal (full text available here):

“While the considerable clinical benefit provided by Ultrapheresis is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits immune mechanisms which mediate tumour cell elimination.”

Their findings proved that soluble TNF receptor (sTNFRI)-secreting tumor cells resisted destruction by TNF:

“These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.”

We have another interesting study published just weeks ago in the journal Clinical Chemistry and Laboratory Medicine that adds more evidence that soluble tumour necrosis factor receptor type I concentrations are a powerful predictor of outcome in breast cancer.

“The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer.”

The authors surveyed cytokines in breast cancer patients including interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)and followed them for ten years. Their data led them to this conclusion:

“…a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer… Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.”

In other words, the soluble TNF receptors, the worse the breast cancer patient will do. But what about other types of cancer? A research article published in the Journal of Surgical Oncology shows the link between serum cytokine receptor levels and bone sarcoma:

“We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors (interleukin 6 (IL-6); interleukin 8 (IL-8); interleukin 10 (IL-10); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); macrophage colony-stimulating factor (M-CSF); granulocyte colony-stimulating factor (G-CSF); interleukin 1 receptor antagonist (IL-1ra); sIL-2R; tumor necrosis factor receptor I (TNF RI), and TNF RII) with clinico-pathological features and survival of patients with bone sarcomas.”

They used multiple metrics to show the association between cytokines and soluble receptors and tumor characteristics along with overall outcome. Their data led to this conclusion:

“These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.”

A research article published in the journal Tumor Biology finds the same kind of evidence for colorectal cancer. While they found a correlation with a number of circulating cytokines, their summary observations are the most striking:

sTNF RI (soluble TNF receptor 1), IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF RI was found elevated in the greatest percentage of all CRC [colorectal cancer] patients, in the greatest proportion of stage I patients and presented the best diagnostic sensitivity. In addition, the sTNF RI level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor.”

And another paper published in the same journal concludes with concordant evidence for solid carcinomas in general:

“…for the soluble tumor necrosis factor (TNF) receptors type I (p55) and type II (p75) and IL·2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors plasma levels of TNF receptor p75 and IL·2 receptor were not significantly different from the controls.”

A study published around the same time in the journal Oncology makes the same case for non-small cell lung cancer (NSCLC) as well, with an interesting comparison to the standard markers:

“…increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers…A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor.”

We also have the evidence from a study published in the journal Cellular Immunology in which the authors blocked the decoy effect of soluble tumor necrosis factor receptor type I (sTNFRI)receptors with neutralizing antibodies and observed the effect. Their data led to this conclusion:

“These data demonstrate that sTNFRI directly influences tumor formation and persistence in vivo and suggest the selective removal and/or inactivation of sTNFRI as a promising new avenue for cancer immunotherapy.”

Obviously an intervention that gets rid of the ‘decoy’ receptors so the immune system can effectively attack the tumor makes excellent sense. In a paper published in the Proceedings of the National Academy of Sciences (USA) we have early evidence that the soluble tumor necrosis factor receptors can be filtered out of the blood of human cancer patients:

Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro.”

The investigators proceeded to show that the blocking factor is derived from malignant cell membrane TNF receptors. They further observed that:

“Purified BF blocks the lytic [malignant cell destroying] activity of recombinant human and mouse TNF-alpha…The BF also inhibits the necrotizing activity of recombinant human TNF-alpha… The BF may have an important role in…interaction between the tumor and the host antitumor mechanisms…”

A paper published in 2002 by a leader in the field of immunepheresis in the journal Therapeutic Apheresis and Dialysis documents the emerging insights and outstanding outcomes with cancer patients that were already being accomplished:

Immunosuppression is a hallmark of advanced malignancies in man. Over the past 40 years, many investigators have identified soluble immunosuppressive factors in blood, serum, ascitic fluid, and pleural fluid from cancers in man and other species. Suppressive factors have also been identified that are produced by tumors.”

The author also draws attention to the similarity of immunologic tolerance in cancer and pregnancy (which has also been referred to as the ‘trophoblastic theory‘):

“The description of immunosuppressive factors in the blood of vertebrates who either have cancer or who are pregnant is significant, for only in pregnancy and cancer does a seemingly normal immune system tolerate immunogenic neoantigen. Tumor necrosis factors (TNFs) are …thought to be suppressed in patients who have cancer or who are pregnant. Recently, elevated blood levels of soluble tumor necrosis factor receptors (sTNFRs) have been reported in the blood in a variety of cancers and pregnancy.”

He notes that much evidence has accumulated validating the connection between elevations of sTNFRs and a poor prognosis:

“In 1990, after our initial publication of the discovery of sTNFRs in the serum and low molecular weight ultrafiltrates of serum from a variety of cancer patients, others confirmed significant elevations of sTNFRs in cancer patients. This elevation was found to correlate with a poor prognosis.”

The author then reviews the suppressive role of soluble receptors shed from tumor cells and the positive effects of ultrapheresisfiltering the blood to remove reduce these suppressive molecules. A few years a ago a paper published in the same journal reported advances in the filtering technology:

“Using these methods, an improvement in performance status and clinical symptoms and reduction of tumor size have been observed.”

Two years ago further advances and positive clinical outcomes were reported in Therapeutic Apheresis and Dialysis in a paper presented by the same pioneer mentioned above:

“Mean reductions in sTNF-R1 (48%), sTNF-R2 (55%), and sIL2-R levels (72%) were observed … Clinical findings indicated tumor inflammation and necrosis in most patients. Side-effects were low-grade fever, flu-like symptoms; tumor pain and redness, warmth, tenderness, and edema. The column demonstrated safety and efficacy in lowering plasma sTNF-R1, sTNF-R2, and sIL2-R levels.”

Personally I know of patients who have undergone this procedure who have had outstanding outcomes characterized by dramatic reductions in tumor mass.

Is this a safe treatment? A paper published in the Journal of Clinical Apheresis reports that, in contrast with chemotherapy, short term side-effects of immune activation were only mild-moderate, and there were no long-term side-effects at all:

“The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment…Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects.”

Immunepheresis (therapeutic apheresis, ultrapheresis) is worthy of far more research resources and clinical utilization. For more information see the International Immunology Foundation. Treatment is available for suitable candidates from M. Rigdon Lentz, M.D. (an American oncologist and immunepheresis pioneer) and Kiran Lentz, M.D. at their clinic in Prien am Chiemsee, Bavaria, Germany. As usual, the papers presented above are a small selection from a much larger body of literature. A 170 page report by Dr. Ralph Moss of Cancer Decisions on the work of Dr. Lentz is available here.

Note: Removal of soluble receptor blockade to permit immune destruction of malignant cells is an elegant physiological intervention to reduce tumor burden. Practitioners and patients alike must also bear in mind the need to investigate and treat from a functional medicine perspective the underlying causal factors that develop malignancies in the first place and promote their recurrence.

These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.