…” 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)”:
- 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.
- “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]
- 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.
- 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.
- 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.
- 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
- A systematic overview of chemotherapy effects in
indolent non-Hodgkin's lymphoma.
Acta Oncol. 2001;40(2-3):213-23. Review. PMID: 11441933
