Advocacy > Advocacy Issues 

Can vaccine-induced, tumor-specific responses predict clinical benefit?

…” the mechanism of action on a surrogate is critical to the type of inference one can draw,…” 
Antiviral Drugs Advisory Committee - Jay P. Siegel, M.D.,  CBER

The following contains questions and patient perspectives that relate to patient-specific vaccines and other immune-based therapies for the treatment of some incurable lymphomas.  The key stimulant for the text within is this: We believe that given the preliminary data from independent groups, including safety data and what is known about the mechanism of action of active immunity, that there is a reasonable certainty that vaccine-induced, tumor-specific humoral and/or cellular responses can predict clinical benefit for a significant number of patients.

Background:

As you know, indolent follicular non-Hodgkin’s lymphomas (fNHL) are not curable with standard treatments. At diagnosis, pts with fNHL are often advised to watch and wait until the disease progresses to a point that causes symptoms or when it transforms and becomes aggressive.  Median survival is about 7 to 10 years. During this time patients who receive treatment are suffering side effects from the current standard of care. Cumulative toxicity from chemotherapeutic agents, the most frequently prescribed therapeutics for indolent lymphomas, includes damage to major organs, cognitive function, and bone marrow reserve, as well as long-term immune damage specific to the numbers, diversity and function of T-cells. We also know that surviving malignant cells can adapt in response to chemotherapy, become refractory, and grow faster. Common mechanisms of chemotherapy agents include: DNA-alteration, interaction with DNA, interference with cell growth, and DNA repair enzyme inhibition.

Patient perspectives about patient-specific vaccine therapies:

Informed patients understand the limitations of systemic standard treatments for the treatment of fNHL and look to immune-based therapies as a potential way out of the cycle of standard treatments. Importantly, immune-based therapies provide three clear advantages: (1) They are highly unlikely to contribute to mutations, (2) they give the opportunity to safely intervene early in the course of disease by capitalizing on less impaired innate immune mechanisms, and (3) they provide a promising way to safely consolidate standard treatments.

Our growing focus on the importance of access to immune-based therapies is based on good data from independent groups, and an appreciation that acquired NHL-specific host immunity can provide a more lasting, less toxic, and more natural defense against lymphoma. We believe these interventions will allow many of us to avoid treatments with consequences that can make us susceptible to secondary problems, including secondary cancers and opportunistic infections. Patients are also alarmed to realize that initial treatment with chemotherapy regimens has not improved survival for fNHL, and, importantly, these regimens can potentially undermine the ability of the immune system to respond to immune-based therapies.

Because of the reported progress by independent research, we consider watchful waiting to be a missed opportunity for many of us in which we unnecessarily allow the disease to grow and spread and accumulate mutations and further depress immune function. We also consider initial treatment with standard chemotherapy as slamming the door on important new treatment opportunities. Consider that from our perspective when standard treatments do not cure and have major toxicities, they are also, in truth, experimental, stopgap measures.

Although we are encouraged that phase III trials of Idiotype vaccines are under way to validate the findings of earlier studies, we have concerns about the time that these trials will require to find answers using Time to Progression or Survival as primary endpoints. We also have ethical concerns about many of the randomized trial designs, summarized in an attachment. 

In the remainder of this text, we will give the reasons why there is a reasonable certainty that vaccine-induced, tumor-specific humoral and/or cellular responses can predict clinical benefit, which we define as follows:

(1) slowing tumor progression, (2) stabilizing tumor progression,  (3) regressing tumors (4) causing significant delays in relapse or time to progression when used as a consolidation therapy, (5) enhancing subsequent complementary immune-based therapies, and (6) curing some patients.

We believe that the following circumstances, facts, and evidence – considered as a whole – allow for the responsible use of immune response as a surrogate endpoint for the approval of patient-specific vaccines.

1) Circumstance: There is an urgent need for alternatives to standard treatments described in the background section above. This current standard of care is unacceptable given the promise and the safety profile of Idiotype immune-based therapies, specifically idiotype vaccines. See for example, Each Subsequent Therapy Results In Diminishing Response Rate And Duration Of Response In Low Grade Or Transformed Low Grade Non-Hodgkin's Lymphoma. ASCO 2001 Abstract 1165

2) Proof of concept: Active immune protection is the foundation of health and survival against antigens. There is no need to provide proof of concept for this mechanism. Instead we need only to validate that the mechanism is generated by the intervention.

3) Disease characteristics: The characteristic waxing and waning of follicular NHL suggests that may be particularly responsive to immune intervention.  So-called spontaneous regressions of fNHL have been reported are commonly associated with prior immune activation in patients. See, for example, Spontaneous regression in non-Hodgkin's lymphoma: clinical and pathogenetic considerations. PMID: 2660545

4) Something important to build on: There is also data that clinical benefit, even if minimal, could form the foundation for benefit from subsequent complementary treatments. For example, “six patients with disease progression after primary DC vaccination received booster injections of Id-KLH protein, and tumor regression was observed in 3 of them (2 CRs and 1 PR).” See Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients.
Blood. 2002 Mar 1;99(5):1517-26. PMID: 11861263

We want to underscore that an immune response to tumor-antigens is at the very least something important to build on, just as lowering blood pressure or cholesterol levels is a positive benefit in the treatment of heart disease.

5) Tests of immune response to tumor are reliable and correlate with efficacy: Tests, such as ELISA, that measure humoral immune response to tumor-specific antigen, both before and after vaccine interventions are reliable and correlate with clinical benefit in numerous studies by independent groups. See Table -1 that follows and this example from the literature: “Patient vaccination with tumor associated protein antigens can increase tumor-specific CTLp frequencies. The correlation of increased tumor specific CTLp with freedom from progression is significant at P = .002. See Tumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin's lymphoma.” Blood. 1996 Jul 15;88(2):580-9. PMID: 8695806

6) Important evidence of clinical benefit: The passive administration of Anti-idiotypic antibodies are also generated by the patients own immune system following anti-idiotypic vaccination.  It is believed that the anti-idiotypic antibody response developed following vaccination should be more efficacious and durable then that obtained by passive antibody administration antibodies.  See for example, Anti-idiotype antibodies can induce long-term complete remissions in non-Hodgkin's lymphoma without eradicating the malignant clone. PMID: 9694706

7) Evidence of delayed time to progression: Correlations between measures of immune response to delayed time to progression in clinical trials provides a reasonable certainty that this activity predicts clinical benefit in at least some patients.

TABLE -1

8) A strong correlation between immune response and clearance of  a molecular marker for fNHL: Patient-specific vaccines have induced immune response that correlate strongly with molecular remissions (clearing of detectable translocations in the patients blood) in a recent study. See Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999 Oct;5(10):1171-7. PMID: 10502821

An excerpt from the abstract: “All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions.” Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission.

In conclusion, we understand that the mechanism of action is vital to the inference about a surrogate endpoint, and that there is no controversy about the value of the mechanism of active immunity for the survival of humans and animals alike. For patient-specific vaccines we already have (1) the ability to test for immune responses, including an established standard for testing humoral responses (ELISA); (2) evidence of clinical benefit correlated with measured immune responses from a variety of independent study groups, including animal studies; and (3) a conceptual and clinical basis for accepting that this type of intervention will not preclude the use standard treatments and may well complement subsequent immune-based interventions. 

Finally, we are also concerned about the criteria used for approval in current randomized trials. As an example, will patient-specific vaccines be denied approval if the benefit is seen to be modest overall – some benefiting, some not, the median being slightly better, as an example?  Here we believe we must again state that scientists can build on even "modest" benefits by sequencing vaccine treatments with interventions that can compliment an immune response, such as Rituxan, changes in dose and dose scheduling, Interferon, IL-2, CpG, other vaccines, and other interventions that may fix a dysfunctional immune system, or amplify it. So how good does the treatment need to be to get started?  When will patients have access to patient-specific vaccines?  Can we do better?

Sincerely,

- Karl  Schwartz
President, Patients Against Lymphoma

See also:  Attachment on issues pertaining to current randomized trials that follows. We believe these issues fit into this discussion as part of the context that speaks to the need for surrogate endpoints in clinical trials of immune-based therapies.

Attachment

Summary of Grievances on Randomized Trial Design for Id-vaccines

Patients who receive the placebo (KLH unbound to the patient-specific protein)”:

1. Receive a surgical resection of a lymph node for no other purpose than to protect the blind. This procedure carries some risk, such as infection and/or permanent Lymphedema.
2. “Spend” an aggressive combination treatment (CVP) without receiving what appears to be the best aggressive combination therapy, CHOP + Rituxan or CVP + Rituxan. Many lymphoma experts consider the initial treatment to be the most important for producing a durable response. CVP (Median TTP ~15 mo. based on numerous large studies) does not compare well with CHOP + Rituxan (Median TTP ~ 63 mo. for 38 pts) [1]
   
   NOTE: There is an additional concern that aggressive combination therapies are best reserved for transformation events, which are common for indolent lymphomas. “Development of transformed cell lymphoma is one of the most common features of the aggressive phase of indolent lymphoma.” [2], What is more, combination chemotherapy such as CVP have not demonstrated improved survival for indolent NHL as described in a recent systematic overview: “There is no proof that initial combination chemotherapy will prolong survival in comparison with single drugs.” [3]
3. Receive an initial treatment that can compromise their ability to benefit from emerging immune-based therapies, including the Idiotype vaccine should it win approval. Patients consider this to be a high “price of admission” for a 66% chance to receive the vaccine.
4. Are not provided with a crossover opportunity if they relapse. Presumably crossover is not provided in order to find out if there is a survival benefit for the vaccine group. But, patients in both arms will use other treatments, including other vaccines, when they relapse, and this will confound the assessment of survival benefit in any event.

1. Czuczman M, Grillo-Lopez A, White CA, et al. Progression free survival after six years median follow-up of the first clinical trial of rituximab/CHOP chemoimmunotherapy. Program and abstracts of the 43rd Annual Meeting of the American Society of Hematology; December 7-11, 2001; Orlando, Florida. Abstract 2519.
    
2. Malignant lymphomas of follicular center cell origin in humans. V. Incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma. Cancer. 1984 Mar 1;53(5):1109-14. PMID: 6692302
   
3. A systematic overview of chemotherapy effects in indolent non-Hodgkin's lymphoma.
   Acta Oncol. 2001;40(2-3):213-23. Review. PMID: 11441933