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CancerGuide: Special Kidney Cancer Section

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LipoNova Tumor Lysate Vaccine
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An Adjuvant Tumor Lysate Vaccine From Germany

This simple and virtually non-toxic vaccine is the first ever adjuvant treatment for RCC to achieve statistically significant (though overall modest) benefits in a randomized controlled clinical trial. It is on the way to becoming an approved treatment in Europe. Although it's not guaranteed it will arrive at this destination, this vaccine may become the first adjuvant therapy in routine use for kidney cancer anywhere in the world. It is available now under limited circumstances. The vaccine is made by a German Company called LipoNova (Note that they have an English version of their site).

The Treatment

This simple vaccine consists of minimally processed tumor cells from the patient's kidney tumor. The cells are incubated with gamma interferon, broken apart (lysed), and frozen. Patients then receive an injection into the skin every four weeks for at least six months starting four weeks after their surgery.

The idea is to stimulate the immune system against the tumor by putting tumor fragments within reach of dendritic cells which live in the skin. Dendritic cells are a type of antigen presenting cell, and under the right conditions, activate the rest of the immune system about a threat.

The History

There have been two major trials of this treatment.

  • The first trial was not a randomized trial, but rather a historical controlled single institution trial. Initial reports were first reported in 1997 [Repmann 1997] and five year results were reported in 2003 [Repmann 2003].

  • The second trial was a large multi-institutional randomized trial with over 500 patients. Patients were randomized between vaccine and observation. This trial started to enroll patients in 1997 and final results were reported in the prestigious medical journal, The Lancet, in early 2004 [Jocham 2004] with at least 4 1/2 years of follow-up for all patients.

The Good News

  • No Side Effects: There are virtually no side effects from this treatment! Most patients experience no side effects. A very few had mild flu-like symptoms or mild redness and swelling at the injection site.

  • Efficient Vaccine Production: Unlike some other vaccines, they were able to produce vaccine for a very high percentage of patients. In the randomized trial they were able to make the vaccine for 95% of patients.

  • Positive Results

    • The Historical Controlled Trial Had Striking Results, Particularly for T3 Tumors:
      • For patients with T2N0M0 tumors, estimated 5 year survival was 86% for the vaccine group compared to 71.4% for the historical control. Progression free survivals were 84.6% for the treatment group and 65.3% for the control group.
      • For patients with T3N0M0 tumors, estimated 5 year survival was 77.5% for the vaccine group compared to 25% for the historical control. Progression free survivals were 68.2% for the treatment group and 19.4% for the control group. This is spectacular!

    • The Randomized Study had More Modest (But Still Positive) Results:
      • Overall, there was a modest benefit. The vaccine group had 77.4% progression free survival at five years compared with 67.8% for the control group and the difference between the survival curves as a whole was statistically significant. This was mostly due to benefit for patients with T3 tumors, while patients with T2 tumors had only a small benefit which wasn't statistically significant. There were more T2 patients than T3 patients in the study (over 2:1 ratio T2 Patients:T3 Patients) so the overall results were more influenced by the T2 patients than the T3 patients.
      • For patients with T2 tumors: Vaccine patients did just slightly better than control patients with 81.3% five year progression free survival compared to 74.6% for control patients. Comparison of the survival curves as a whole was not statistically significant though the treatment group's survival curve is consistently just a little better than the control group's over the length of the curve.
      • For patients with T3 tumors: The vaccine had a real benefit with 67.5% progression free survival at five years for the vaccine group compared with 49.7% for the control group. I think this is a substantial and meaningful difference. The difference between the difference between the curves overall was statistically significant, but just barely so (p=.04). These survival curves show clear separation early on which widened over the first few years and then remained roughly constant for the rest of the length of the study.

  • Some Notes

    • The randomized trial only tested the vaccine in patients with T3 or T2 tumors, and this was determined postoperatively. Patients who were thought to have T3 or T2 tumors before surgery but who turned out not to weren't treated. As a practical matter you would decide whether be treated before your surgery, and there would be little reason not to be treated, if it were possible, even if you had other than T3 or T2 disease. The exception would be if it turned out you had something other than renal cell cancer, such as a benign tumor, or metastatic or inoperable disease which would require other treatment.

    • The definition of T2 tumors used in the randomized trial was the 1993 definition which meant tumors larger than 2.5cm otherwise confined to the kidney. The current definition of T1 includes tumors up to 7cm in size, so in effect, this trial treated many "T2" patients who would now be considered T1. Actually a majority of their "T2" patients would be considered T1 today. If this treatment is available to you, and your tumor is larger than 2.5cm, the data on "T2" tumors applies to you even if you're considered to have a T1 tumor. However, keep in mind that the benefit for "T2" tumors was rather modest anyway.

    • The vaccine might actually be about as effective in preventing recurrences in T2 tumors as in T3 tumors among patients who are actually destined to suffer a recurrence. If the vaccine reduces the risk of recurrence in those patients who are destined to recur by a the percentage for either T3 or T2 tumors, it will make less of a difference in T2 patients overall simply because fewer are going to recur anyway. When you actually look at it this way using five year progression free survival as the benchmark, the lower recurrence rate for T2 tumors accounts for most of the apparent difference in efficacy of the vaccine between T2 and T3 tumors. The remaining difference is small and could be due to chance. So biologically the vaccine may well be about as effective in T2 tumors as it is in T3 tumors, even though on an absolute basis, it makes less of a difference for patients with T2 tumors. Finally, there is no strong reason to think smaller tumors would produce micrometastases which are less susceptible to immune attack than larger tumors.

    • Both the T3 and T2 groups in the randomized trial included patients with positive lymph nodes who are at much higher risk of recurrence, but there were only a few node positive patients so this couldn't have affected results much. Among the 11 patients with positive lymph nodes there was no hint that vaccine patients did better, but the sample size is way too small to be sure of anything there. The historical controlled trial didn't include node positive patients.

    • This report of the randomized trial made no attempt to discern any effect of subtype of RCC on the results. It is possible that the results are more promising or less promising for various subtypes. Clear cell RCC is thought of as the subtype most susceptible to immune therapy and it'd be interesting to know if the vaccine made a greater difference in clear cell RCC.

    • In the randomized trial, treatment consisted of six injections at four week intervals but in the historical controlled trial, treatment was continued for as long as there was vaccine material - up to 30 months. LipoNova's website says that, "Vaccination with tumour vaccines is given at regular intervals of 3-4 weeks, usually up to six times, sometimes more often." I don't think these differences account for the better results in the historical trial since the difference appears to be that the control group did better in the randomized trial than in the historical trial.

The Caveats

  • No Proven Biological Effect: With adjuvant therapy all you see are statistical differences in relapse rate. An adjuvant therapy is more plausible if the treatment is known to work at least to some degree advanced cancer where tumors can be seen to shrink or disappear. Proof of specific activation of the immune system would also be useful. But here we have neither.

  • Borderline Statistical Significance: While the study had statistically significant differences in progression free survival, they were close to the limit of statistically significant. The limit for statistically significant is p=.05 which roughly means 5% of the time you'd get just as good results by chance. Here for all treated patients the overall difference was statistically significant at p=0.02, for T3 patients it was significant at p=.04 and for T2 patients, not statistically significant at p=.22) This means there is still a small chance that the results are only due to chance though that's still not likely. But this also means that there is a fair amount of uncertainty about just how great the benefit is and there is a risk the benefits of vaccine, while real, are smaller than the trial results indicate due to bit of good luck. It's also possible the benefits are greater than the trial results indicate. There is uncertainty.

Availability

LipoNova, the vaccine's sponsor, has already applied to the European Medicines Agency (EMEA) for marketing approval and expects approval in early 2005. The EMEA is Europe's equivalent of the US FDA. Of course, approval is not guaranteed. I certainly don't know enough about EMEA to speculate whether they will approve or not. Certainly given the lack of side effects of this treatment and the probable benefit, it's hard to see how withholding this treatment could be in the interest of patients, despite any uncertainty.

Meanwhile, it turns out that the treatment is actually available now under some circumstances. If you can pay for the vaccine, LipoNova will make it. This will cost 18,000 Euros which you will have to pay yourself. According to LipoNova, German patients may be reimbursed if the vaccine is approved (which again cannot be guaranteed). Also for German patients, LipoNova will store frozen tumor from which the vaccine can be made at no charge so that if their vaccine is approved, you can then have the vaccine made without charge to you. One concern here is the delay before vaccine is administered while waiting for approval during which time metastasis may be growing beyond the point at which the vaccine can control it. Another is whether vaccine made from frozen tissue will really be the same as vaccine made from fresh tissue.

I understand that if you are not from Germany it may be possible to have your surgery at home and have tumor for vaccine production sent to LipoNova by courier. Whether this would quick enough from overseas is not entirely clear. It is also not clear how difficult it might be to bring the prepared vaccine home for injections (which would be easy to give anywhere). I presume it would be no problem in the EU. If you're interested, I recommend contacting LipoNova for further information, obviously before your surgery.

This information is from a LipoNova press release and communication with Dr. Christian Doehn, one of the investigators on the randomized study.

The Bottom Line

I think the difference in recurrence rates in T3 RCC are substantial and worth fighting for. If it looked like I had a T3 primary tumor or a large tumor, I would be willing to travel to get this treatment and I would be willing to pay for it, if I could. Although there is room for some doubt about its benefits, this treatment is apparently almost completely non-toxic, and there is no better proven adjuvant therapy for RCC at this time. The benefit for less than T3 tumors is much more modest, and I don't think "extreme measures" are justified to obtain this treatment with smaller tumors, although if it's easily available, there seems to be nothing to lose, again given that it is essentially non-toxic.

A Few More Speculations and Thoughts

If you have metastatic disease and are pursuing surgery for limited metastatic disease I think this vaccine might turn out to be useful combined with the surgery. Even though surgery is one of the best treatments for metastatic disease when all metastases can be removed, the risk of having a recurrence after surgery for metastatic disease is very high - higher even than for T3 tumors. To the extent that patients who have had all detectable metastatic disease removed have micrometastatic disease similar to what earlier stage patients have, it makes sense that this treatment should be equally effective. The higher prevalence of micrometastatic disease among metastatic patients who've had surgery could mean the vaccine would help a higher percentage of these patients. If you are left with micrometastatic disease after surgery, as most patients are, then I see no reason this wouldn't reduce the recurrence risk. If you've already had your kidney out, I don't know whether LipoNova would make a vaccine from a metastatic tumor.

Finally, this vaccine is probably relatively weak. I haven't heard of a simple lysate vaccine having any real effect on advanced RCC. This study gives every reason to hope that more powerful and more effective vaccines can be developed for adjuvant therapy of RCC. This includes vaccines which use "adjuvants" - substances added to enhance the immune response, dendritic cells, and possibly IL-2 or Interferon.

References

Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C.
Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial.
Lancet 2004 Feb 21;363(9409):594-9. [PubMed Abstract (will open in new window)]
Repmann R, Wagner S, Richter A.
Adjuvant therapy of renal cell carcinoma with active- specific-immunotherapy (ASI) using autologous tumor vaccine.
Anticancer Res. 1997 Jul-Aug;17(4B):2879-82. [PubMed Abstract (will open in new window)]
Repmann R, Goldschmidt AJ, Richter A.
Adjuvant therapy of renal cell carcinoma patients with an autologous tumor cell lysate vaccine: a 5-year follow-up analysis.
Anticancer Res. 2003 Mar-Apr;23(2A):969-74. [PubMed Abstract (will open in new window)]


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This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: April 3, 2004, Last Updated: May 17, 2004