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1 JANUARY 2009 I VOLUME 113, NUMBER 1
● ● ● CLINICAL TRIALS
Comment on Di Nicola et al, page 18
Cancer
vaccines: up, down, … up again?
---------------------------------------------------------------------------------------------------------------Sattva S. Neelapu and Larry W. Kwak
THE UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER
In this issue of Blood, Di Nicola and colleagues report that vaccination of relapsed
indolent non-Hodgkin lymphoma patients with DCs loaded with killed autologous
tumor cells induced a multifaceted immunologic response that correlated with objective clinical responses including 3 continuous complete responses lasting beyond 45 months.
espite the promise of harnessing the immune system to target cancer cells, most
phase III trials of cancer vaccines have been
disappointing. Potential reasons for these failures, despite the high immunogenicity of vaccines,1 may be categorized into factors affecting the afferent or priming phase of the
D
immune response and factors influencing the
efferent or effector phase of the immune response. For instance, during the afferent phase
of the immune response, it is possible that the
magnitude of the T-cell response or the avidity of the induced T cells was not sufficient to
kill tumor cells effectively after vaccination.
Combination immunotherapeutic strategies for cancer. The afferent or priming phase of the immune
response may be enhanced by vaccines using novel tumor antigens or adjuvants or by vaccinating stem
cell transplant (SCT) donors with healthy immune systems with the goal of adoptive transfer of the
antitumor immunity to the patient. The efferent or effector phase of the immune response may be
augmented by inhibiting various immunosuppressive and tolerance mechanisms in the tumor microenvironment. Potential strategies that are in various stages of preclinical and clinical development are shown.
These agents may be used in combination with therapeutic cancer vaccines for optimal induction of
antitumor immunity that, in turn, may lead to improved clinical outcome. MDSC, myeloid-derived
suppressor cells; TGF-␤, transforming growth factor beta.
blood 1 J A N U A R Y 2 0 0 9 I V O L U M E 1 1 3 , N U M B E R 1
During the efferent phase of the immune response, it is possible that the antitumor T cells
may not have trafficked to the tumor site or if
they trafficked, they may not have been able to
overcome newly recognized immunosuppressive mechanisms present in the tumor
microenvironment.
However, indolent B-cell non-Hodgkin
lymphomas may be different from many other
solid tumors, as they are considered highly
immune responsive. In the current study, vaccination with dendritic cells (DCs) loaded
with autologous heat-shocked, irradiated, and
ultraviolet-C–treated lymphoma cells induced
both T-cell and B-cell tumor-specific immune
responses. As opposed to other vaccination
strategies targeting a single tumor antigen, this
vaccine formulation can potentially induce
immune responses against multiple tumorassociated antigens and thus may minimize
immune escape. Moreover, vaccination
skewed the maturation of the T cells to effector memory and/or terminally differentiated
phenotype, activated natural killer cells, and
intriguingly, reduced the number of
CD4⫹CD25⫹Foxp3⫹ regulatory T cells in the
peripheral blood and/or tumor microenvironment. Aside from minor quibbles with specificity controls, the assays used by Di Nicola et
al to measure immune responses were state-ofthe-art and appeared to correlate with clinical
responses, as has been described for other hematologic cancer vaccines.2,3 Collectively, the
enhancement of multiple immunostimulatory
signals and down-modulation of the immunoregulatory elements of the immune system
may explain the higher objective clinical response rate (33.3%) observed with this and
another previously reported DC vaccine formulation4 compared with non-DC vaccine
formulations.5 However, the clinical responses
were induced primarily in patients with low
tumor burden, suggesting there may be opportunity for further optimization of vaccine
strategies to eradicate disease in patients with
large tumor masses prior to vaccination. Recent discoveries in basic immunology have also
1
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now provided us several novel agents to augment both the afferent and efferent phases of
the immune response following therapeutic
vaccination. The afferent phase of the immune
response could be enhanced by using more
potent vaccines with novel adjuvants, such as
Toll-like receptor ligands, or by vaccinating
donors of transplant recipients who have a
healthy immune system as opposed to patients
who may be immunocompromised either from
the cancer or from therapy.3 Alternatively,
vaccines could be used in combination with
agents that inhibit the immunosuppressive
mechanisms such as coinhibitory receptors/
ligands6 and/or deplete regulatory T cells7 to
augment the effector phase of the immune
response.
The natural history of development of a
novel therapeutic modality is often marked by
initial enthusiasm (up) followed by periods of
discouragement (down), as obstacles are encountered. The promising results reported by
Di Nicola et al, the recent approval of a heat
shock protein vaccine (vitespen) in Russia for
the adjuvant treatment of patients with renal
cell carcinoma at intermediate risk of disease
recurrence,8 and advances in understanding of
immune tolerance suggest that we may be very
close to overcoming these barriers to success
for therapeutic cancer vaccines.
Conflict-of-interest disclosure: S.S.N. declares no competing financial interests. L.W.K. is
a consultant for Antigenics Inc. ■
REFERENCES
1. Neelapu SS, Kwak LW, Kobrin CB, et al. Vaccine induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med. 2005;11:986-991.
2. Qazilbash MH, Wieder ED, Thall PF, et al. PR1 peptide vaccine-induced immune response is associated with
better event-free survival in patients with myeloid leukemia
[abstract]. Blood. 2007;110: 90a. Abstract 283.
3. Neelapu SS, Munshi NC, Jagannath S, et al. Tumor
antigen immunization of sibling stem cell donors in multiple
myeloma. Bone Marrow Transplant. 2005;36:315-323.
4. Timmerman JM, Czerwinski DK, Davis TA, et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma:
clinical and immune responses in 35 patients. Blood. 2002;
99:1517-1526.
5. Park HJ, Neelapu SS. Developing idiotype vaccines for
lymphoma: from preclinical studies to phase III clinical
trials. Br J Haematol. 2008;142:179-191.
6. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic
melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043-6053.
7. Dannull J, Su Z, Rizzieri D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after
depletion of regulatory T cells. J Clin Invest. 2005;115:
3623-3633.
8. Wood C, Srivastava P, Bukowski R, et al. C-100-12
RCC Study Group. An adjuvant autologous therapeutic
vaccine (HSPPC-96; vitespen) versus observation alone for
patients at high risk of recurrence after nephrectomy for
renal cell carcinoma: a multicentre, open-label, randomised
phase III trial. Lancet. 2008;372:145-154.
● ● ● TRANSPLANTATION
Comment on Alexander et al, page 214
Resetting
the clock
---------------------------------------------------------------------------------------------------------------Gabor G. Illei
NATIONAL INSTITUTES OF HEALTH
In this issue of Blood, Alexander and colleagues describe the reversal of the abnormalities in adaptive immunity following ASCT for SLE. These much needed data
provide mechanistic support to immunoablative therapeutic approaches in SLE.
he rationale for autologous hematopoietic
stem cell transplantation (ASCT) in systemic autoimmune diseases, such as systemic
lupus erythematosus (SLE), is based on 2 major assumptions. The first is that the immunoablative conditioning regimen will lead to
deletion of autoreactive cells of the adaptive
immune system and, second, that the regenerating immune system will be (more) tolerant to
self-antigens; in effect, “resetting the immunologic clock” to a pre-autoimmune state.1
Although over 100 patients with severe,
treatment-resistant lupus were reported to
T
2
have undergone ASCT,2,3 there are very
scarce data about the impact of ASCT on the
underlying pathologic processes. The key
question is whether ASCT fundamentally
changes the abnormal immune response observed in SLE. Alexander et al address this
question by performing a detailed phenotypic
analysis of T and B lymphocytes and autoantibody responses in 7 patients before and after
ASCT. At baseline, patients exhibited abnormalities characteristic of active lupus, such as
lymphopenia, restricted T-cell repertoire,
dominance of memory versus naive T and
B cells, expansion of plasmablasts and
high-titer autoantibodies. Conditioning with
cyclophosphamide and rabbit antithymocyte
globulin (ATG) achieved the expected lymphodepleting effect. The novelty of the paper
is the careful analysis of the regenerating adaptive immune system showing the reversal of
all, and normalization of most, baseline abnormalities, albeit with different kinetics. The
authors confirmed the previously described
normalization of the restricted T-cell repertoire by 1 year after transplantation but also
provided a description of the kinetics of this
normalization. They observed an initial expansion of memory T cells immediately after
transplantation (driven by exogenous antigens), followed by an increased output of recent thymic emigrants starting around
6 months after transplantation that led to a
diverse, normal-looking T-cell repertoire.
Similarly, there was a dramatic shift in B-cell
subpopulations from memory to a naive B-cell
dominance after transplantation with disappearance of circulating plasmablasts, a hallmark of active lupus.4 Accordingly, antidsDNA antibodies, which correlate with
disease activity in lupus and are thought to be
secreted primarily by plasmablasts, disappeared in all patients. The disappearance of
protective vaccine-specific antibodies suggested an effect on long-lived antibodysecreting cells, which are thought to also secrete other autoantibodies, such as antinuclear
antibodies and anti-Ro/SSA and anti-La/
SSB. Similar to vaccine-specific antibodies,
antinuclear antibodies either disappeared or
decreased significantly. Interestingly, antiRo/SSA and anti-La/SSB levels persisted in
the 2 patients who had these antibodies at
baseline, which is especially intriguing because
1 of these patients flared 18 months after transplantation. The reason for the persistence of
these antibodies is unclear but may reflect the
resistance of some long-lived plasma cells or a
difference in the availability or presentation of
various autoantigens after transplantation.
The clinical significance of this observation
remains to be determined. There are a few
limitations to the study. First, the number of
patients is relatively low, but the long
follow-up and the consistency of findings
among the 5 patients with lasting remissions
strengthen the results. The observation that
CD4⫹CD25brightFoxP3⫹regulatory T cells
return to the range seen in healthy controls
1 JANUARY 2009 I VOLUME 113, NUMBER 1
blood
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
2009 113: 1-2
doi:10.1182/blood-2008-10-184523
Cancer vaccines: up, down, … up again?
Sattva S. Neelapu and Larry W. Kwak
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