Prof. Larry W. Kwak
Department of Experimental Transplantation and Immunology,
Medicine Branch, Division of Clinical Sciences,
NCI, Bethesda, Maryland.

Dear Dr. Kwak:

The enclosed letter was written to you only and has been endorsed by one hundred and sixty members of NHL-other, a not-for-profit support group that serves patients and family touched by Non-Hodgkin’s Lymphoma. In addition, we believe many more persons will endorse this letter in the near future. This letter was signed and prepared by many persons including several MD’s.

Although we have done our best to research the issues involved, we recognize that the issues are complex. Therefore, we will wait for your response before forwarding to the directors of the National Cancer Institute, who may be more responsible for the design of the study we are questioning.

I’d like to emphasize that we are on the same side in the battle against this disease, and we would be glad to meet with you to discuss how to further support your invaluable efforts with you.

Sincerely,

Karl L. Schwartz

Prof. Larry W. Kwak
Department of Experimental Transplantation and Immunology,
Medicine Branch, Division of Clinical Sciences,
NCI, Bethesda, Maryland.

Dear Dr. Kwak:

First, I want to thank you for the dedication you bring every day to the fight against NHL which causes more than 20,000 deaths a year in the United States. Your talents and commitment have earned our respect and appreciation.

On behalf of an Internet support group for NHL patients with 160 members from across the nation, I’m writing to propose an expansion in your idiotype vaccination trial for follicular non-Hodgkin’s lymphoma to benefit more patients.

With conventional therapies (chemotherapy and radiotherapy) the disease remains essentially incurable; the survival rates do not change significantly for untreated patients. Due to the poor prognosis, innovative treatments are needed. Your recently published paper (Nature Medicine, 5(10): 1171-77, 1999) provides impressive clinical, cellular and molecular data suggesting that your vaccination protocol produces a significant therapeutic improvement. The majority of these patients cannot wait 5, 10 or 15 years for more definitive conclusions about your vaccination protocol.

We believe the rights of cancer patients participating in clinical trials must be explored from angles other than the purely scientific. Scientists also should apply "good medicine" whenever possible (Kaufman, D.; CA Cancer J Clin, 44(2): 109-14, 1994). Your recently announced idiotype vaccine trial for the treatment of follicular NHL contains clinical rules, which trouble us.

Example 1 -- Throwing it away: Our understanding is that participants in your study will not receive the vaccine if they do not obtain a complete remission (CR), or at least achieve minimal disease, from chemotherapy. We believe that the vaccine should be used to treat the patient anyway. We believe the study can continue without "contamination" by simply not considering the results in these cases.

Put yourself in the patient's place: You undergo surgery to remove a tumor. You worry about the procedure for creating the vaccine. You endure chemotherapy and its risks. You discover the chemotherapy has failed to optimally reduce the tumor amount required to ensure the ideal conditions for the success of the vaccine. Finally, you're denied the right to try the vaccine that could very well save or extend your life. NOTE: There is evidence that a small number of patients with a partial remission (PR) will benefit from the vaccine. Dr. Ronald Levy's group reported some efficacy of the idiotype vaccine on patients in PR (Hsu et al., Blood, 89:3129-3135, 1997). Five of 20 patients in PR developed immune response against the idiotype vaccine; 1 of these was stable, 2 had tumor regression and 2 had tumor progression at the time of publication. Alternatively, with better coordination among investigators, these patients should be allowed to change to another protocol like the dendritic idiotype vaccine, a variation of your study that has been shown to work in 4/4 patients with "measurable residual disease" (Hsu et al., Nature Medicine, 2:52-58, 1996).

Example 2 -- Why use people to test a proven vaccine against an adjuvant and carrier? The team plans to give the vaccine to two-thirds of the study participants. This plan "will make the trial more attractive to patients'' as mentioned by Dr. Kwak. We appreciate the benefit to science of giving one group the vaccine, while giving a second group a similarly promising therapy, to see which is best. However, we don’t understand the point of giving one group the adjuvant and carrier—agents that are unlikely to give protection against the tumor. Again, put yourself in the patient's place: You're asked to participate in a study that includes surgery and chemotherapy. You endure chemotherapy and its risks. You endure all of that only to receive the adjuvant and a carrier instead of the idiotype vaccine, which has been proven to work in a significant number of patients.

Our understanding of the rational behind the idiotype vaccine is that the idiotypic protein is a weak immunogen and that the physical linkage to the carrier (a potent immunogenic, in this case KLH) is required for a specific anti-idiotype immune response to occur. This specific immune response is increased by immunologic adjuvants, such as CM-CSF, that probably recruit and activate antigen-presenting cells (APCs).

Studies in mice have already shown that immunization with GM-CSF (or KLH) even if mixed (not coupled with a potent immunogenic) with the idiotypic protein, is unable to induce a specific immune response, or to confer protection against tumor challenge. All mice that received GM-CSF (or KLH) mixed with the idiotypic protein died from tumor progression. In contrast mice immunized with a fusion idiotypic protein had greatly increased survival time when challenged with tumor cells containing the same idiotype, but died when challenged with tumor cells with a different idiotype. These studies fully support the notion that the patients receiving only GM-CSF and KLH will not mount a specific immune response against the tumor and will have no benefit from the vaccination.

Today, the basis of cancer immunotherapy is the specificity of the immune response against the tumor, and not unspecific immune-stimulation. Finally, based on what is known so far about the adjuvant, it is unlikely that their use alone will result in any relevant clinical benefit. We believe your expectations are the same; otherwise, the control arm of the study would include half the participants, instead of one third.

Therefore, in our opinion, the use of the adjuvant alone to treat follicular NHL is not ethical in this human study because it compares an untested and probably ineffective agent with an effective and safe vaccine.

NOTE: Two studies (Hsu et al., Blood, 89:3129-3135, 1997; Bendandi et al., Nature Medicine, 5(10):1171-1177, 1999) using 2 different adjuvants have shown evidence that the idiotype vaccine is effective in inducing a specific immune response against the tumor idiotype in a great number of patients. These results also suggest that it is not the adjuvant that is playing the major role in the induction of a specific immune response against the idiotype protein. Bendandi et al. (1999) concludes: "Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival." Hsu et al. (1997) concludes: "This study ... shows that the ability to make such an immune response is correlated with a more favorable clinical outcome." One of the studies even shows molecular remissions in these patients (Bendandi et al., 1999).

Example 3 -- Why exclude previously treated patients? It’s unfair to exclude the patients who need the most help from the most promising immunotherapy available today. This policy is like offering an inferior life preserver to a drowning person (and forbidding the use of the best). Instead, this exclusionary policy provides the best hope only to those who are swimming. When you have an incurable disease, all therapies (approved and otherwise) are experimental. All patients must have a right to participate in studies that offer the best chance for survival. Therefore, we believe the exclusion of all previously treated patients from your promising vaccine therapy is unfair. NOTE: Even after the first remission, follicular NHL patients frequently respond to chemotherapy and are able to obtain a complete remission (CR). Nine of the 41 patients included in the trial results published by Hsu et al., (1997) were in their second or higher remission. Although the number of patients was small, this study shows that even after several chemotherapy treatments all patients were able to mount an immune response to the KLH (the carrier protein), and some were able to mount an immune response against the idiotype antigen. Furthermore, the results show that the most important factor for an immune response to the vaccine was the presence of CR and not the fact of being in first, second or later remission.

Example 4 -– Why require chemotherapy in all cases? All participants in your study must receive chemotherapy prior to receiving the vaccine. Sometimes, this means waiting for the disease to progress enough to justify the administration of the chemotherapy. We believe it is unethical to conduct such studies in humans because it does not consider what is in the best interest of the patient. We believe alternate protocols should be designed to administer the vaccine without using chemotherapy when patients have minimal disease. If the vaccine alone does not do the job, chemotherapy could then be administered, followed with the same vaccine.

NOTE: It is now firmly established that chemotherapy has many potential side effects, including the development of a second malignant tumor, even more aggressive and dangerous than NHL.

CONCLUSIONS: We believe the best interests of the patients should be paramount when designing clinical trials. (1) Since studies show the idiotype vaccine can benefit patients who did not obtain a complete response from chemotherapy, it would be wrong to deny them this opportunity in your study. Perhaps you can design a separate protocol where such patients can receive the vaccine. (2) It is clearly unethical to test a proven vaccine against an unproven adjuvant and carrier. Each arm of this study (and all studies) must have an equivalent potential to benefit the participants. (3) Because of the extraordinary potential of the idiotype vaccine therapy, additional studies should be made available to previously treated patients who are most in need. (4) We also believe it’s wrong to require chemotherapy before receiving the vaccine in all cases. For some patients, the vaccine can be given first, and then chemotherapy followed by a second administration of the vaccine can be given if needed.

Finally, we propose the expansion of your promising clinical trial to include more patients. Because the production of the idiotype protein is expensive, we also propose the reinforcement of your budget, and we will do all that we can to help you achieve this. Can you please comment on these important issues?

Thank you for your attention to this matter.

Sincerely,