* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Cancer vaccines: up, down, … up again?
Survey
Document related concepts
Social immunity wikipedia , lookup
Herd immunity wikipedia , lookup
Molecular mimicry wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Pathophysiology of multiple sclerosis wikipedia , lookup
Multiple sclerosis research wikipedia , lookup
Immune system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Adaptive immune system wikipedia , lookup
DNA vaccination wikipedia , lookup
Sjögren syndrome wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Vaccination wikipedia , lookup
Innate immune system wikipedia , lookup
Immunocontraception wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Transcript
From www.bloodjournal.org by guest on June 17, 2017. For personal use only. insideblood 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 From www.bloodjournal.org by guest on June 17, 2017. For personal use only. 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 Updated information and services can be found at: http://www.bloodjournal.org/content/113/1/1.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.