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Immunomodulators

 

The following are generally short articles, all presented together on this page, most recent first.

: Rituxan plus Leukine (GM-CSF)

: Boosting Rituxan Therapy with CSFs

: Colony Stimulating Factors in Cancer Therapy

: Rituxan plus IL-2:  Phase I Clinical Trial

: Interferon Alpha-2b as Single Agent in CLL

: Combination Immunotherapy with Rituxan and IL-2

: Immunomodulators to Boost the Efficacy of Rituxan

: Rituxan and Interleukin-2

Rituxan and Interleukin-2

10/6/02

by Chaya Venkat

The abstract below describes work to further improve the performance of Rituxan. This work is being done at Dana Farber. It reports on NHL clinical trials, but can CLL be far behind?

Basically, the idea is this: One of the major mechanisms by which Rituxan causes cancer cells to die is by tagging the CD20 on the cancer cell, which makes the cell a much more attractive target for killing by the immune system. Rituxan paints a big red bulls-eye on the cancer cell, so to speak, and it can no longer hide as well from the just wrath of the immune system. This mode of killing is called antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC works better when there are more of the immune system cells that can do the killing, so called "effector cells". Interleukin-2 is believed to expand the population of these effector cells. Combinations such as these hold promise for further improvement in the efficiency of Rituxan. 

Incidentally, Interleukin-2 (also Interleukin-15, I believe) is being studied as a way of increasing the number of cytotoxic T-cells (CTLs) in the body, as a way of beefing up the body's own immune system, especially in combination with other immunotherapy and vaccine approaches.

Abstract:

Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma.

Friedberg JW, Neuberg D, Gribben JG, Fisher DC, Canning C, Koval M, Poor CM, Green LM, Daley J, Soiffer R, Ritz J, Freedman AS.

Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 

Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1.2 MIU/m(2)/d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m(2)) was given on d 15, 22, 29 and 36. The regimen was well tolerated and  only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8+ and CD56+ lymphocytes in all evaluable patients (P = 0.0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody- related infusional toxicity. Further studies of this rational combination are warranted and ongoing.
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Immunomodulators to Boost the Efficacy of Rituxan

10/18/02

by Chaya Venkat

Rituxan as frontline single agent therapy is very attractive to a lot of us, because it is not your standard issue chemotherapy drug. It is the first monoclonal antibody that has been approved for NHL, and hopefully soon to be approved for CLL as well. The side effects from the infusion are relatively mild, and generally limited to the first infusion for most patients. Unlike older chemotherapy drugs such as Fludarabine and Cyclophosphamide, Rituxan is thought to be less damaging to the bone marrow. 

The problem is that Rituxan does not do a thorough job by itself. Complete remissions are few and far between, and there are no PCR negative responses in CLL patients using Rituxan as single and frontline therapy, not to my knowledge. The punch is much, much stronger when Rituxan is combined with other chemotherapy drugs such as the famous RFC (Rituxan, Fludarabine and Cyclophosphamide) combo. But this gets us right back to worrying about the toxicity of the "F" and "C".

Now come some welcome new studies that suggest we can boost the efficiency of Rituxan by combining it with some well known immune boosters. True, the study is about NHL, but I would be willing to bet similar trials are underway for CLL as well.

Remember, majority of the cancer cell killing in Rituxan therapy is done by the body's own immune system, the monoclonal tags the cancer cells and thereby paints a big "kill me" sign on them, making them more readily recognized and attacked by the immune system. Well, it stands to reason that in  CLL patients with compromised immune systems, anything that boosts the immune system is going to help the efficiency of Rituxan. Below is a PubMed abstract that describes combining Interferon alpha, and Granulocyte colony stimulating factor (G-CSF) with Rituxan to boost the efficiency.

Interferon alpha has been used for several years now, it is a man-made copy of a substance that is made naturally by some types of white blood cell. Interferon is a natural product in the body, made as part of the immune response when the body reacts to cancers or viral infections. It has two main modes of attack, it interferes with growth and proliferation of cancer cells, and it boosts the production of killer T cells and other cells that attack cancer cells. Interferon is also thought to facilitate cancer cells to put out chemical signals that make them better targets for the immune system. Interferon has been used in recent years for several different types of cancer, particularly kidney cancer, melanoma, multiple myeloma, and some types of leukemia. It is also used to treat viral infections such as hepatitis. You can read a lot more about it by clicking on the link below:

Link: Interferon background

The other component, "Granulocyte Colony Stimulating Factor" (G-CSF) does what its name implies, it stimulates the production of granulocytes (neutrophils are of interest here).

There are going to be more of these immunotherapy combinations in the future, combining various cytokines, colony stimulating factors, monoclonals etc until we get the level of response that we need to control the cancer proliferation. With mild and acceptable toxicity profiles, the issue soon becomes one of managing and controlling the cancer, pretty much as we now manage and control high blood pressure for example, rather than focus solely on total eradication of the enemy. None of us would sneer at going in for a few shots of maintenance regimes such as these, if it means we can lead normal lives for our normal life spans.

Abstract:

Beyond immunochemotherapy: combinations of rituximab with cytokines interferon-alpha2a and granulocyte-macrophage colony stimulating factor.

Kimby E.

Department of Hematology, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden.

Monotherapy with the human-mouse chimeric anti-CD20 monoclonal antibody rituximab is effective and well tolerated in the treatment of indolent non-Hodgkin's lymphoma, but the majority of patients relapse. The combination of chemotherapeutic agents with rituximab results in greater efficacy, but at the cost of the increased toxicity associated with chemotherapy. To increase the efficacy of rituximab without compromising tolerability, the cytokines interferon-alpha2a, which has multiple immunomodulatory effects and enhances antibody-dependent cell-mediated cytotoxicity, and the granulocyte-colony stimulating factor, which enhances antibody-dependent cell-mediated cytotoxicity by neutrophils, have been combined with rituximab. In a randomized comparative study in patients with relapsed or untreated indolent non-Hodgkin's lymphoma, the addition of interferon-alpha2a significantly increased responsiveness to a second course of rituximab in patients with a partial response or minor response to an initial course of rituximab monotherapy. In a single-arm study in 20 patients with relapsed disease, the combination of granulocyte-colony stimulating factor with rituximab resulted in a longer duration of response than normally seen with rituximab monotherapy. In both studies, no significant increase in adverse events compared with rituximab monotherapy was reported. Currently available data suggest that the combination of rituximab with immunomodulatory cytokines result in increased efficacy without compromising tolerability. Copyright 2002, Elsevier Science (USA). All rights reserved.

Semin Oncol 2002 Apr;29(2 Suppl6):7-10
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Combination Immunotherapy with Rituxan and IL-2

10/18/02

by Chaya Venkat

My last article was about combination of Rituxan with Interferon alpha and G-CSF. The logic that went into that article works as well for the study outlined in the PubMed abstract below, using Interleukin -2 (IL- 2) in combination with Rituxan. First, a little bit about this most famous interleukin.

Interleukin-2 (IL-2) has been studied since 1983, when its ability to boost T-cell production made it of great interest in the fight against AIDS. (AIDS virus destroys the T4 cells of the immune system). IL-2 is a cytokine that is produced primarily by the T4 helper cells, and it in turn boosts the production of more T4 helper cells, CD8 cytotoxic cells, antibody producing B cells, natural killer cells (NK), and monocytes/macrophages. There is a snowball effect here, the IL-2 helps produce T-cells, which in turn secrete more of the IL-2, each step feeds the other and so on. This type of a feed-back loop is common in our immune system, it is called an "autocrine loop".

The downside of IL-2 therapy is its toxicity, which is dose dependent. In the early years of AIDS therapy, patients died due to IL-2 toxicity, because the doses were too high. We now know a lot more about dosages and how to control the side effects. These side effects include fevers, chills, rigors, sweats, muscle and joint pains, nausea, vomiting and fluid retention. All of the usual fun stuff that we have come to enjoy and appreciate in therapy. There may be increases in load on liver function, abnormalities in sodium, potassium or other electrolytes.

I expect we will be seeing many more of these fine-tuned combinations of immunotherapy drugs to control if not cure cancer cell proliferation.

Abstract:

Br J Haematol 2002 Jun;117(4):828-34

Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma.

Friedberg JW, Neuberg D, Gribben JG, Fisher DC, Canning C, Koval M, Poor CM, Green LM, Daley J, Soiffer R, Ritz J, Freedman AS.

Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1.2 MIU/m(2)/d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m(2)) was given on d 15, 22, 29 and 36. The regimen was well tolerated and only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8+ and CD56+ lymphocytes in all evaluable patients (P = 0.0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody-related infusional toxicity. Further studies of this rational combination are warranted and ongoing.

PMID: 12060117
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Interferon Alpha-2b as Single Agent in CLL

11/25/02

by Chaya Venkat

If you recall, I had written earlier on combination of Rituxan with Interferon-alpha 2B as a way of boosting the efficiency of the monoclonal antibody. Interferon alpha is also the standard drug for controlling hepatitis C virus (HCV). 

Thus I was disappointed when I came across this abstract (below) that described the effect of Interferon-alpha 2b (IFN-2b) by itself on high risk CLL patients. The study compared three groups of patients: the first group was untreated, early stage (Stage A) patients, but who had poor prognostic indicators (such as diffuse bone marrow infiltration, short lymphocyte doubling time and high serum thymidine kinase levels). This first group was treated with INF-2b. The second group was also similar patients, early stage and poor prognosis factors, but they were just watched, no therapy at all. The third group was untreated, but good prognosis patients, who were also left without any therapy. 

There was no significant difference between the first and the second groups, in progression free survival or overall survival, in other words the IFN-2b made no difference at all. The third group, the ones with the good prognosis, did well as expected. They had significantly longer progression free survival and overall survival. IFN-2b is used effectively in many solid tumors, so there was hope it would have an impact in CLL as well. Apparently not, at least by itself. I have not seen definitive trials indicating that it has unequivocal value in combination with other immunomodulatory drugs such as Rituxan, but the jury is still out on that, I suppose. Nevertheless, this is disappointing information. 

Abstract:

[PubMed - indexed for MEDLINE]

Interferon-alpha 2b (IFN alpha) for early-phase chronic lymphocytic leukaemia with high risk for disease progression: results of a randomized multicentre study. 

Langenmayer I, Nerl C, Knauf W, Dempster S, Hallek M, Adorf D, Dietzfelbinger H, Busch R, Ziegler-Heitbrock HW, Thiel E, Emmerich B.  

Abteilung fur Hamatologie und Onkologie, Klinikum Innenstad, Ludwig- Maximilians-Universitat Munchen, Germany. 

The efficacy of interferon-alpha 2b (IFN alpha) to prolong progression-free (PFS) and/or overall survival (OS) in early B-CLL (Binet stage A) was examined in a risk-adapted phase III study. 99 previously untreated B-CLL patients were recruited. 44 patients with expected high risk for disease progression, defined by non-nodular bone marrow infiltration and lymphocyte doubling time < or = 12 months or serum thymidine kinase levels > or = 5 U/I, were randomized to either receive IFN alpha (group 1, n = 21) or not (group 2, n = 23). 55 low-risk patients were observed to evaluate this risk stratification (group 3). During a median observation time of 36 months, four patients in the IFN alpha group achieved a partial remission (PR), no patient had stable disease (SD), and 17 patients experienced progressive disease (PD). The four responders had less extensive disease at study entry and tended to exhibit a rise in serum IgG levels. In group 2, no PR, seven SD and 16 PD, whereas in group 3, no PR, 37 SD and 18 PD occurred. PFS in group 1 (6.7 months) was not different from group 2 (13.3 months, P = 0.22), but PFS of groups 1 and 2 differed from group 3 (37 months, P < or = 0.001). OS was 44.9 months (group 1), 43.1 months (group 2) and 57.9 months (group 3). OS was not significantly different for group 1 v 2, but was significant between groups 1 and 3 (P = 0.023). The higher percentage of PD in group 2 compared to group 3 (70% v 29%) shows that the selected risk factors allow the definition of CLL stage A patients at risk for disease progression within about a year. In conclusion, our data indicate that IFN alpha does not prolong PFS or OS in stage A CLL patients with high risk for disease progression. 

PMID: 8759897
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Rituxan plus IL-2:  Phase I Clinical Trial

12/18/02

by Chaya Venkat

I was glad to come across this NCI sponsored clinical trial, phase-1, that combines Rituxan and Interleukin-2 (IL-2). (See several previous articles on the subject in CLL Topics to get some of the background information and science). CLL patients are included in the trial, and I believe they are recruiting as we speak. 

Visit the URL below for more information. The study is being conducted at Ohio State University. 

http://clinicaltrials.gov/show/NCT00010192

Announcement of Clinical Trial:

Official Title: Phase I Study of Rituximab Followed by Interleukin-2 in Patients With CD20-Positive B-Cell Lymphoid Malignancy 

Further Study Details: 

OBJECTIVES: 

I. Determine the dose-limiting toxicity of rituximab followed by low-dose and intermediate-dose pulse interleukin-2 (IL-2) in patients with CD20-positive B-cell lymphoid malignancy. 

II. Determine the maximum tolerated dose of intermediate-dose pulse IL-2 in this patient population. 

III. Determine the pharmacokinetics of this regimen in these patients. 

PROTOCOL OUTLINE: This is a dose-escalation study of intermediate-dose pulse interleukin-2 (IL-2). Patients receive rituximab IV on days 1, 8, 15, and 22. Patients then receive low-dose IL-2 subcutaneously (SC) on days 29-39, 43-53, 57- 67, and 71-81, and intermediate-dose IL-2 SC on days 40-42, 54-56, 68- 70, and 82-84. Cohorts of 3-6 patients receive escalating doses of intermediate-dose pulse IL-2 until the maximum tolerated dose (MTD) is reached. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity. Patients are followed every 3 months for 1 year. 

PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study within 1 year.
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Colony Stimulating Factors in Cancer Therapy

2/25/03

by Chaya Venkat

In previous articles we discussed the role of Epoetin, or EPO, to help deal with anemia. Epoetin is one of several major CSFs (Colony Stimulating Factors) that have become available in recent years, using the latest recombinant DNA technologies. 

GM-CSF belongs to a family of cytokines called colony-stimulating factors that promote the production of various blood cells in the bone marrow. GM-CSF regulates the development of neutrophils, macrophages, monocytes and eosinophils. The other CSFs are granulocyte-CSF (G-CSF), which specifically induces neutrophil production, and macrophage-CSF (M-CSF), which stimulates macrophages and monocytes. The pharmaceutical versions of these natural immune cell hormones are produced by genetically altered yeast, E. coli or mammalian cells.

The use of CSFs to treat neutropenia in cancer patients has been long established. Since neutrophils play a major role in fighting microbes such as bacterial, fungi and parasites, patients with neutropenia are particularly susceptible to bacterial and wide spread fungal infections. In a study of GM-CSF in neutropenic cancer patients, the drug was shown to reduce mortality caused by fungal infections. Neutropenia is fairly common among cancer patients. It may be caused by a number of factors including opportunistic infections, nutritional deficiencies (vitamin B12, folate), chemotherapy treatments, several drugs such as Bactrim/Septra, ganciclovir. Both G-CSF and GM- CSF have been shown to increase neutrophil counts in people, but a number of laboratory studies suggest that both GM-CSF and G-CSF do more than just encourage the proliferation of neutrophils. There is a substantial body of data showing that these important cells of the immune system are not only reduced in neutropenic patients, but they may also be functionally deficient and just plain not able to do their job right. The CSFs have shown the ability to restore the function of these damaged cells, enhancing their ability to kill pathogens, microbes etc and antigen presentation. Specifically, GM-CSF-treated neutrophils, monocytes and macrophages have exhibited increased activity against bacteria, fungi, etc, including the dreaded Pneumocystis carinii. 

Here is all you ever wanted to know about Neupogen (G-CSF, generic name Filgrastim). 

Neupogen professional overview 

Another G-CSF is now on the market, called Neulasta. This is supposedly a new improved version of the old favorite, Neupogen. This too is a type of filgrastim, called pegfilgrastim, which lasts longer in the body without getting excreted in the urine, and therefore patients do not need to have as many injections as they had to have with the previous version. 

Neulasta professional overview

And, All you ever wanted to know about Leukine (GM-CSF, generic name Sargramostim) - this is a 30-page product monograph from Immunex, the manufacturer: indications, dosage, reactions, etc. 

Leukine professional overview

You can see that EPO, G-CSF and GM-CSF are likely to be in your future some time, especially if you are heading toward more aggressive chemotherapy regimes, or your CLL is progressing to the point where the bone marrow is not able to produce the required cell lines without some encouragement. For that reason, it is worth saving these links for future reference, even if you don't need the information right now. 

But I have another reason for bringing up this subject now, I have become very interested in how these CSF cytokines can be used to stimulate the immune system, and how than can be combined with Rituxan therapy. More on that in my next article. 

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Boosting Rituxan Therapy with CSFs

2/27/03

by Chaya Venkat

By now we all know that the way Rituxan works is by harnessing the body's own immune defenses against the cancer cells. The major function of Rituxan is to tag the offending cells, making them that much more "visible" to the immune system. We have discussed how complement is an important part of the immune system necessary in killing the cancer cells tagged by Rituxan, via a mechanism called CDC (complement dependent cytotoxicity). There is another mechanism, called ADCC (Antibody Dependent Cellular Cytotoxicity) which is equally important. This mechanism depends upon neutrophils, macrophages, NK cells, T-cells etc to do the killing, once the CLL cells have been tagged by Rituxan. 

But what about patients who go into therapy with poor neutrophil and macrophage counts? Not only is it possible that the numbers of these important cell lines are reduced, but they may also be not functioning properly, because of the confusing propaganda cytokines (chemical messages) put out by the cancer, in an effort to protect itself. Here is one reason why it may be that early stage patients have much better response to Rituxan, than late stage patients whose immune function cells are more compromised, or patients who have already been through prior chemotherapy and are therefore neutropenic. Removing this road block would make response rates to Rituxan therapy for previously treated patients or advanced stage patients that much better. 

If one needs plenty of properly functioning neutrophils and macrophages to make the Rituxan effective, and we now have GM-CSF and G-CSF drugs available that can boost the production of these important cell lines, (please see my previous article today to learn more about CSFs) it does not take a genius to suggest that perhaps it makes sense to combine the two approaches: i.e., treat the patients with CSF drugs, just ahead of Rituxan therapy, in other words get the body to ramp up the production of neutrophils and macrophages, just prior to hitting the cancer with Rituxan.  

Well, I have not seen too many clinical trial results yet, comparing the various CSFs that can be added on to Rituxan therapy, in live human beings. But here is a mouse study that seems pretty detailed. SCID mice (Severe Combined Immune Deficient mice) are mice that have been deliberately bred to have very little immune defenses of their own, and therefore they will pick up any cancer we throw at them. A whole lot of these mice were infected with lymphoma on day zero. They were then divided into 6 groups, and treated with different combinations of drugs. The experiment was conducted to see how long the mice survived. Here is a quick picture of the results: 

Group

Treatment

Survival (days)

A

No therapy

22

B

G-CSF

21

C

GM-CSF

20

D

Rituxan

34

E

Rituxan + G-CSF

49

F

Rituxan + GM-CSF

56+


Within experimental error, treating with just G-CSF or GM-CSF made no difference, the mice died at about the same time as the mice that got no treatment at all. Rituxan made a big difference, the mice lived a lot longer. But the luckiest of the bunch of mice was the group that got both Rituxan and GM-CSF, they are still alive and kicking after 56 days. Pretty dramatic results. Seems to me this is a lead that is worth following, and in fact we have discussed phase-I trials along these lines for NHL patients. Too bad it all takes so long to go through the process, and CLL always seems to lag behind NHL in clinical trials. I would have been even more frustrated if my husband had not responded as well as he did to just plain vanilla Rituxan. Some of you out there with friendly oncologists who are willing to listen to you, you might want to discuss combination of GM- CSF followed by Rituxan therapy, both are well understood, non-toxic and commercially available drugs, and there is a great deal of logic to combining them. 

Abstract:

[588] Concurrent Administration of Granulocyte Colony-Stimulating Factor (G-CSF) or Granulocyte-Monocyte Colony-Stimulating Factor (GM-CSF) Enhance Rituximab's Biological Activity and Upregulate CD11b in a Severe Combined Immunodeficiency (SCID) Mouse Lymphoma Model. 

Myron S. Czuczman, Scott Reising, Elizabeth A. Repasky, Francisco J. Hernandez-Ilizaliturri. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA 

Recent studies performed in SCID mouse models suggest that a predominant percentage of Rituximab's in vivo antitumor activity occurs through antibody dependent cellular cytotoxicity (ADCC) via FcgRIII receptors. Co-expression of CD11b (MAC-1), an adhesion molecule present in activated neutrophils, has been demonstrated to play an important role in the induction of ADCC. Previously, we had shown that neutrophil function is necessary for optimal antitumor activity of Rituximab. (Abstract # 1811, ASCO 2002). 

Objectives: To study the effect(s) of GM-CSF and G-CSF on the biological activity of Rituximab and its correlation to phenotypic changes of CD11b on murine effector cells in a NHL-bearing SCID mouse model. 

Material and Methods: Natural killer (NK) cell-depleted SCID mice were inoculated by tail vein injection with 1x106 Raji cells on day 0. Animals were divided into six cohorts: Group A received placebo; Group B received murine (m)-G-CSF; Group C received m-GM-CSF; Group D received Rituximab alone; Group E received concurrent m-GCSF and Rituximab; and Group F received concurrent m-GM-CSF and Rituximab. Rituximab doses (10mg/kg) were administered via tail vein injection on days +5, +9, +13 and +17. Murine-GM-CSF or G-CSF (10mg/day) were given via intraperitoneal injection two consecutive days before each dose of Rituximab or placebo. Peripheral blood was collected after the second dose of cytokines or placebo in 3 mice from each group and samples were analyzed by flow cytometry for CD11b expression. The end point of the study was overall survival. Statistical analysis was performed with Kaplan-Meier survival curves and P values calculated by log rank test. 

Results: Treatment with G-CSF or GM-CSF led to a 1.5 to 2-fold increase of CD11b expression in neutrophils when compared to placebo. Treatment with G-CSF lead to a higher expression of CD11b on neutrophils (82%) than GM-CSF (63%). No anti-tumor activity was observed among mice treated with G-CSF or GM-CSF alone and their median survival was similar to the placebo group (22 [GpA] vs 21 [GpB] vs 20 days [GpC]). Rituximab alone resulted in significant anti- tumor activity. However, the addition of GM-CSF or G-CSF to Rituximab lead to a significant prolongation in survival (P=0.0487) compared to SCID mice treated with Rituximab alone. Median survival in the Rituximab alone arm was 34 days compared to median survival of 49 to 56+ days in the combination of mAb + cytokine arms (analysis continues). Survival rates were highest among SCID mice treated with Rituximab + G-CSF (100%) followed by animals treated with Rituximab + GM-CSF (40%) at 56 days of observation. 

Conclusions: Upregulation of CD11b occurs after cytokine stimulation and may play an important role in augmenting Rituximab-associated ADCC anti-tumor activity. Concurrent administration of GM-CSF or G-CSF with Rituximab was more effective in controlling lymphoma growth and in prolonging survival than Rituximab monotherapy alone. 

Keywords: Rituximab\ Lymphoma\ G-CSF/ GM-CSF 
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Rituxan plus Leukine (GM-CSF)

5/12/03

by Chaya Venkat

I have been interested for a long time in CLL clinical trials using a combination of Rituxan as front-line therapy with various immunomodulatory drugs such as GM-CSF (Sargramostim, brand-name Leukine), Interleukin-2, CPG-ODN and beta Glucan. You can look up a number of articles on each of these topics on this website, so I will not belabor the logic again in this article. There have been announcements of clinical trials along these lines for NHL, but none that I knew of that included CLL patients, barring the one at Sarah Cannon that I wrote about a couple of days ago, that included relapsed "SLL/CLL" patients. I had heard rumors to the effect that a new clinical trial using Rituxan plus GM-CSF will begin soon at M. D. Anderson. Today I was happy to get confirmation of that from Dr. Keating. This clinical trial will start in the next couple of months at M. D. A. 

Those of you who are looking at start of therapy soon and are considering Rituxan as front-line therapy, you might want to consider this clinical trial. GM-CSF (granulocyte macrophage colony stimulating factor, some of you may be more familiar with the brand name "Leukine") is well known, well understood drug used to support patients with immune suppression; specifically, reduced neutrophils and macrophages. It is unlikely in my opinion that addition of this immune boosting drug will hurt the excellent toxicity profile of Rituxan. On the other hand, one of the major hurdles in using Rituxan as single agent therapy in CLL has been that compared to diseases like Follicular Lymphoma, the response rates have been significantly lower in CLL. Using an immune system booster such as GM-CSF in conjunction with Rituxan may make the difference. I am not a big fan of Phase-I trials, but this is one where I think the risks are small (Rituxan alone versus Rituxan plus GM-CSF) and there could be substantial reward in improved response. 

I do not know if this trial is open only to previously untreated ("naive") patients, or if they will accept patients who have been through prior Rituxan only therapy. If you have been through Rituxan before, and are getting ready for a maintenance course of the drug again in the near future, this might be worth looking at; especially if you had less than stellar response the first time and would like to try and improve your odds the  second (or third) time around.

M. D. Anderson has a lot of influence in the CLL community. When we were getting ready for my husband P. C's therapy (Rituxan, front-line and single agent), our local oncologist was initially less than enthusiastic about our choice, and it was not at all clear she would go along with us. A positive response from our M. D. Anderson specialist (Dr. Keating) and a copy of the protocol used by Dr. Deborah Thomas at M. D. A, made it much easier to convince her we were not crazy. I guess it took some of the weight of doing "unorthodox therapy" off of her shoulders and provided her with cover. Last I heard, she is now quite enthusiastic in her support of Rituxan as single agent and front-line therapy for her other CLL patients. 

We all have to learn to some extent how to deal with these sorts of situations, how to grease the wheels, so to speak. Next time around, when/if it is time for P. C. to go back for a re-do of the Rituxan, I have no doubt that the fact M. D. Anderson is doing this clinical trial will have a positive impact in convincing our local oncologist to go along with us, if that is the direction we choose at that time. Since both Rituxan and Leukine are commercially available drugs with proven track records of their own, it should be possible to get action going along these lines outside of formal clinical trials. That is no small consideration for those of us who do not live close to major CLL consortium centers, have less than accommodating health insurance HMOs, or just plain do not want the strict adherence to guidelines and protocols involved in a formal clinical trial.

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