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Caudill & Li HSPPC-96: a personalised cancer vaccine
Oncologic, Endocrine & Metabolic
HSPPC-96: a personalised cancer vaccine
Marissa M Caudill & Zihai Li
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, USA HSPPC-96 is a protein peptide complex consisting of a 96 kDa heat shock protein (Hsp), gp96, and an array of gp96-associated cellular peptides. Immunisation with HSPPC-96 induces T-cell specific immunity against these peptides; gp96 is not immunogenic per se. The non-covalent binding of gp96 to peptides is neither selective nor restricted to cell types. Thus, the collection of gp96-associated peptides represents the antigenic peptide pool of a cell; this is the basis of the peptide-specific immunogenicity elicited by HSPPC-96. Since the repertoire of antigenic peptides in the cell is different between normal and tumour cells and is also distinct among tumours of the same histology due to the randomness of tumour-specific mutations, a purified sample of HSPPC-96 can only effectively immunise against the tumour from which it originates. The immunisation effect is, therefore, specific to both the individual patient and the tumour type. This true custom-based vaccine has been shown to induce protective T-cell immunity against a variety of tumours in animal models. The major mechanism of action is thought to be the ability of HSPPC-96 to prime peptide-specific MHC class I-restricted CD8+ T-cells by interacting with antigen-presenting cells in a receptor-dependent manner. HSPPC-96 is now being widely tested against human malignancies for which effective therapies do not exist. The major challenges of the human studies are immunological monitoring and the determination of optimal dosing, scheduling and route of administration. HSPPC-96 has been well tolerated at all dose levels. Clinical applications are being addressed by numerous studies including an international, multi-centre, double-blind Phase III trial for the treatment of stage III renal cell carcinoma in the adjuvant setting. Keywords: cancer vaccine, gp96, heat shock protein, HSPPC-96 Exp. Opin. Biol. Ther. (2001) 1(3):539-547
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Introduction Mechanism General strategy for clinical applications Dosage and schedule Safety and tolerability Clinical trials Expert opinion Bibliography
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1. Introduction Despite the tremendous advancements in cancer biology research, the main weapons against this devastating disease remain surgery, radiation therapy and the rather non-selective cytotoxic drug therapy known customarily as chemotherapy. With a few exceptions, such as testicular cancer, childhood leukaemia and Hodgkin’s disease, the outcomes of most human malignancies are currently no better than they were three decades ago . The renewed interest in the concept of immunotherapy against cancer is due to the following three principles : • critics have not yet been able to disprove the concept that tumours are the consequence of failed immunosurveillance by the immune system 539 2001 © Ashley Publications Ltd. 1471-2598
it is still unclear what prompts peptide dissociation in vivo. this was strong evidence that antigen-specific peptides were present in gp96 preparations [9-12]. The stoichiometry of gp96 to peptide binding is still unclear. a minimal peptidebinding site of gp96 was recently defined . heparin. is in fact due to associated peptides [5. Biol. although gp96 does bind to ATP and has intrinsic ATPase activity. Additionally. to se c r e t e pro-inflammatory cytokines and to upregulate the Exp.9. which is involved in the folding and unfolding of cellular proteins . passive immunisation or modulation of the immunological climate by systemic therapy with cytokines or other immunomodulating agents HSPPC-96 was first isolated in a murine fibrosarcoma cell line called Meth A. The broad spectrum of substrates is consistent with the notion that Hsps interact with their substrates © Ashley Publications Ltd. loosely through hydrophobic associations . protease mapping and microsequencing. it was found serendipitously that heat treatment of gp96 allowed the protein to bind with exogenous peptides. which are one of the mo s t p o w er fu l AP C typ es . Mechanism 2. By this method. All efforts so far to unload gp96 in another physiological way have not met with much success. Like other Hsps. it is now known that gp96 is a bona fide protein chaperone and is a member of the Hsp family. Opin. All rights reserved. the amount of peptide in the complex required to elicit T-cell immunity is several orders of magnitude less than what would be required if free peptides were used alone .6]. gp96 can interact directly with numerous substrates such as collagen. In addition. several important questions remain to be answered.2 HSPPC-96 interacts with antigen-presenting cells HSPPC-96 immunisation has several unique features. it was shown that Meth A-derived gp96 but not gp96 from another tumour or from normal tissues. or antigens that are preferentially expressed by the tumours (such as early embryonic antigens) • the adaptive immune system can be manipulated or optimised by vaccination. It took nearly 10 years to realise that gp96 exists as a proteinpeptide complex and the immunogenicity of gp96. ATP has not been shown to affect peptide binding to gp96 in vitro (Z Li. immunoglobulin heavy chain and glycoprotein of herpes simplex virus. unpublished). Also. No structural mutation of gp96 itself has ever been identified. Finally. This paper aims to examine the principle of immunotherapeutic strategy with HSPPC-96. The first showed that disruption of HSPPC-96 with a mild acid led to the liberation of peptides. Indeed. It operates independently of adjuvant in mouse models .10]. (2001) 1(3) 2. Moreover. which could be identified by structural analysis as well as immunological assays using peptide-specific cytotoxic T-lymphocytes (CTL) activity as a read-out [5. it is also unknown how the peptides associated with gp96 are eventually transferred to MHC class I molecule in the cell . The immunisation effect of HSPPC-96 is also exquisitely dependent on phagocytic cells . 2. In the process of identifying tumour specific antigens capable of immunising Balb/c mice to mediate rejection of Meth A . can immunise mice against challenge with live Meth A tumour cells. These features together suggest that HSPPC-96 might bind to a receptor-like molecule on the surface of professional antigenpresenting cells (APC) which then present gp96-bound peptides to induce optimal T-cell priming . along with cross-linking. Therefore. bacterial antigens or other model antigens) were able to immunise mice against these antigens. Ther.540 HSPPC-96: a personalised cancer vaccine • tumours are indeed recognisable by the immune system because they express either tumourspecific antigens (such as viral antigens and oncogene products). which could be measured by gel electrophoresis or other biophysical means . . Since gp96 is expressed abundantly in both tumour cells and normal tissues. Despite these advances. it was found that soluble gp96 can stimulate dendritic cells. like that elicited by other Hsps. it was thought that tumour specific mutations of gp96 were the basis of the observed tumour-specific immunogenicity . Related to this.1 HSPPC-96 carries antigenic peptides gp96 is the most abundant protein in the lumen of the endoplasmic reticulum (ER) . The binding of peptides to gp96 was confirmed by the following studies. The role of gp96 in facilitating protein folding was suggested initially by the finding that the introduction of misfolded protein in the ER increases the expression of gp96. gp96 isolated from cells containing known antigens (viral antigens. It will highlight the immunological properties of this molecule and update the experience so far in the clinical development against human malignancies.
CD91 is a complex molecule and its mechanism of action may not be so straightforward.25]. such as tumour. Although the binding does not seem to lead to any functional consequences in platelets. (2001) 1(3) . an 88 kDa scavenger receptor. which mandates the presence of antigen in the context of the same MHC molecules in both the T-cells and the target cells. APCs are activated to the ‘priming mode’ due to increased cell surface expression of co-stimulatory molecules and the secretion of pro-inflammatory cytokines. in h ib its m acrop hages from r e-p r e s en ti n g gp96-chaperoned antigenic peptides . The only evidence that HSPPC-96 may be able to prime CD4+ T-cells comes from functional studies. At high doses.3 HSPPC-96 antigens from the target cells have to be released exogenously and then cross-presented to the T-cells by APCs which possess the proper MHC molecules. Thus far. However. HSP70 fused with a model peptide can also prime CD8 + T-lymphocytes in a CD4 + T-cell independent manner [24. whether or not these T-cells are antigenspecific. 2. researchers have not identified any MHC class II-associated peptide epitopes from HSPPC-96. to homogeneity . unpublished). Meth A-derived HSPPC-96 generates CD4+ T-cells in immunised mice. Interestingly.Caudill & Li 541 expression of co-stimulatory molecules such as CD86 and MHC class II [19. 2. The mechanism of cross priming in the case of gp96 is not entirely clear. It is unclear. It is important to make a distinction between direct and cross priming of CD8+ T-cells. Microsequencing of this molecule by mass spectrometry confirmed it to be CD91. In this case. gp96 was shown to bind some receptor-like molecules on the surface of APCs in a saturatable and competitive manner . Binder et al. The extracellular HSPPC-96 may then interact with APCs through a specific gp96 receptor such as CD91 or CD36. a protein known as α2-macroglobulin receptor or low density lipoprotein-related protein (LRP). In addition. APCs pulsed with Meth A HSPPC-96 can stimulate a Meth A-specific CD4+ T-cell clone to produce cytokines (Matsutake T and Srivastava PK.20]. There is evidence that CD91 may not be the only surface molecule that interacts with gp96. Cross priming was originally described as the priming of CD8+ T-cells by target cells that do not share the same MHC alleles as the antigen specific T-cells . it has been shown that gp96 also binds to platelets . the © Ashley Publications Ltd. however. Two events then ensue. Second. although longer peptides of over 20 amino acids can be successfully charged to gp96 in vitro. it is prudent to keep in mind Exp. Biol. Therefore.7. viral.5 Non-immunological function of HSPPC-96 Surprisingly. Further evidence to support CD91 as a receptor for gp96 is that α2-macroglobulin. A polyclonal antibody raised against this protein can block the representation of gp96 chaperoned peptide to MHC class I. mode of T-cell activation. if not exclusive. By using affinity purification with a gp96-conjugated column. minor histocompatibility and bacterial antigens. personal communications). were able to isolate a cell surface ligand (receptor) for gp96 from a macrophage cell line. may present some of the peptides associated with gp96. led to the conclusion that the priming of Meth A tumour-specific CD8+ T-cells by HSPPC-96 is independent of help from CD4+ T-cells . the peptides of HSPPC-96 are unloaded within the cell and eventually presented on MHC class I molecules. RAW 264. however. Ther. which has the capacity to bind to longer peptides. it is conceivable that MHC class II. First. a previously known CD91 ligand. All rights reserved. HSPPC-96 immunisation activates a subset of CD4+ T-cells that have a suppressive phenotype . One possibility is the release of HSPPC-96. 2. Can HSPPC96 present the peptides to MHC class II pathway and thereby activate CD4 + T-cells? Sequencing by Edman degradation of the pooled peptides from gp96 showed that the average length of gp96-associated peptides is around 12 amino acids (Z Li. It has also been found that gp96 binds less efficiently to APC from mice that have homologous deletion of CD36. Recent data have confirmed that cross priming is the predominant. such as adhesion or activation. in addition to the appropriate co-stimulatory molecules. The depletion of various subsets of T-cells before and during the immunisation period with Meth A-derived HSPPC-96. either from cell death or stress . Antigens from non-haematopoietic cells can be released and then taken up and presented by the professional APCs to T-cells . suggesting that CD36 may be another receptor for gp96 . Opin. providing strong evidence that this could well be the main method of gp96-mediated peptide delivery to APCs. Direct priming strictly means direct activation of naïve T-cells by antigen expressing target cells.4 HSPPC-96 primes CD4+ T-cells primes CD8+ T-cells HSPPC-96 immunisation can prime CD8+ T-cells against many intracellular antigens.
From this preliminary trial. 5/6 patients progressed after immunisation with 2. There are at least two reasons to explain this difference . (a) Obtain tumour (by surgery or other means) from the patient. The general strategy is thus given the acronym ‘OTHER’. although CD4+ T-cells seem responsible for the suppression . two weekly injections of tumour-derived HSPPC-96 led to protection against subsequent tumour challenge. tumour-bearing animals have to be vaccinated with HSPPC-96 more often in order to slow down the tumour growth. A and B. More than 200 patients have now been tested by this OTHER approach worldwide. Opin. route were 1 μg. As mentioned previously. There were significantly more treatment failures in both the 2. weekly for a total of four injections. doses higher than the optimal dose can even cause antigenspecific immunosuppression in a manner that is still unclear. in order to generate effective immunity against tumour A. it is conceivable that multiple injections of HSPPC-96 will have to be given. sc. Using HSPPC-96 purified from a Meth A fibrosarcoma. the grade. A total of 42 patients were initially enrolled in this study. HSPPC-96 has to be delivering the peptides specific to tumour A. this truly custom based and unprecedented approach has become feasible. The primary goals of each phase are: • Phase I: to define maximum tolerated dose (MTD) • Phase II: to monitor efficacy • Phase III: to define long-term risks and benefits HSPPC-96 is an autologous protein-peptide complex. tumour A could only immunise against itself. This demonstrated clearly that tumours are antigenically distinct from one another. 25 and 100 μg of autologous tumour-derived HSPPC-96 given id. not tumour B. 4. . of whom 38 had enough HSPPC-96 purified from resected primary tumours to be included in the study. The schedule of HSPPC-96 administration is also not yet optimally defined. In contrast. as shown in animal studies . definable in this case. using two histologically identical tumours in mice. Since HSPPC-96 purification is now standardised and tumours are often routinely excised for diagnostic or therapeutic purposes. it was appreciated that effective tumour immunity is exquisitely specific. weekly. Exp. a Phase I study was performed using patients with stage IV renal cell carcinoma. (2001) 1(3) 3. We can now speculate that this observed phenomenon is most likely due to the difference in peptide pools as a result of random mutations in the transformed cell. whereas 3/4 patients remained tumour free at dose level of 25 and 100 μg per injection . All rights reserved.542 HSPPC-96: a personalised cancer vaccine that many possible functions of HSPPC-96 have not been completely characterised. It is not directly cytotoxic. i. stepwise. There were no significant toxicities observed.5 μg id. As early as the 1940s. underscoring the fact that HSPPC-96 does have a narrow therapeutic window . the dosage of 25 μg per injection seemed to be optimal. due to the different composition of peptides associated with gp96. To determine the optimal human dose of HSPPC-96. so MTD may not be © Ashley Publications Ltd. even in the adjuvant setting. too great a tumour burden may out-weigh the antitumour responses. meaning. Depending on the different types of tumour. Second. Therefore. HSPPC-96 vaccine is individually based and truly tailored towards an individual tumour from an individual patient . Therefore.. high dose is clearly not optimal for HSPPC-96. differentiation stage or genetic background. Biol.5. First. 2. As of May 2000. (b) HSPPC-96 extraction in the laboratory. The study looked at three different doses. A similar study is being done for gastric cancer patients who have had gastric surgery with curative intent. The optimal doses for intradermal. HSPPC-96 should also be expected to be individually unique. 10 μg and 50 μg respectively . Ther.e. and ip. it was found that the optimal dose to immunise mice against Meth A challenge varied depending on the route of administration. since microscopic metastases are common in cancer patients even when the primary disease is no longer detectable. General strategy for clinical applications Unlike traditional cancer drugs. In addition. In the preclinical animal models.5 μg and 100 μg groups. T-cells from tumour-bearing animals may be tolerant to the tumour antigens since tumour cells do not express co-stimulatory molecules. Dosage and schedule Drug development for use in human cancer treatment must progress through different phases. not against tumour B and vice versa . even at the 100 μg dose level. (c) Return (or reinjection) of HSPPC-96 to the patient.
Thus. two experienced hot flushes after each immunisation. (2001) 1(3) . pancreatic cancer or non-Hodgkin’s lymphoma. In the first pilot trial . sarcoma • a recently re-launched pancreatic cancer trial It is important to point out that the primary objectives of all of the trials except the Phase III renal carcinoma trials are feasibility and toxicity. the follow-up for all studies is still not long enough to be conclusive. None of these patients mounted significant titre of the following auto-antibodies: antinucleoprotein antibody. six out of twelve patients had increased MHC class I-restricted IFN-γ-producing CD8+ T-cells specific against autologous tumours or tumour membranes as measured by an IFN-γ ELISPOT assay. Similarly. only published results will be summarised. In four patients. HSPPC-96 plus IL-2 for renal cancer. In addition. Immunisation was performed weekly using 25 μg HSPPC-96 per dose. patients were carefully monitored clinically and serologically. Three patients reported mild hot flushes between 30 . Moreover.48 minutes after immunisation. Clinical trials There are a total of 11 clinical trials on HSPPC-96 to date. perinuclear or cytoplasmic antigens after HSPPC-96 immunisation. four patients experienced stabilisation of their disease for 3 . Therefore. eight out of thirteen patients had expanded NK cell population by flow cytometric analysis of CD16+ and CD57+ cells. 16 patients with various advanced malignancies (seven gastrointestinal tract.1 The HSPPC-96 pilot study In the pilot study. or enrolment completed (dose defining trial on stage IV renal cancer. Ther. without the need for medical intervention.20] • autoimmune phenomena as a consequence of T-cell activation against the self-peptides in HSPPC-96 Studies have shown so far that these potential side effects do not occur. One patient died 4 days after the second immunisation. one breast. which was determined to be due to the progression of his disease. accompanied by a strong and specific Exp. All rights reserved. To comply with the ethical and scientific standard.Caudill & Li 543 5. thyroglobulin. 6. which had become refractory to established therapies. 6. colorectal cancer. two hepatocellular. at this point there is no evidence of acute HSPPC-96 induced side effects due to self-destructive immune reactions. Efficacy is not the end point for these studies. while one experienced them again only after the second immunisation. one mesothelioma and one unknown primary).g r a de non-Hodgkins’s lymphoma. pain or fever occurred during the immunisation period. Biol. © Ashley Publications Ltd. however their onset was unrelated to the timing of immunisation and the events were attributed to tumour progression. were treated with autologous tumour-derived HSPPC-96. Clinically. Of interest. These trials are classified into three categories. The final category includes five active trials that are still enrolling patients. antibody to dsDNA or ssDNA. dose-defining studies for colorectal cancer and melanoma). No unacceptable toxicities or autoimmune phenomena were observed. which involved 16 patients with various cancers treated with 25 μg HSPPC-96 . all patients had refractory metastatic disease and had exhausted other therapeutic options . HSPPC-96 has been shown to be very safe and well-tolerated. it is premature and even prohibitive to comment on the efficacy of HSPPC-96 at this early stage of clinical development. Patients were injected sc. one pancreatic. Safety and tolerability Theoretical risks of HSPPC-96 injections are: • endotoxin-like reaction due to the secretion of pro-inflammatory cytokines such as TNF-α as a result of the activation of APCs [19. First is a pilot trial that has been completed and reported. no significant adverse effects have been observed in subsequent trials on renal cell carcinoma. gastric cancer. three thyroid. The second category includes five trials that are either closed (pancreatic cancer). gastric cancer. antibodies to m ito c h o n d ria. melanoma. They are: • one Phase III adjuvant therapy study for renal cell carcinoma • s everal P h as e II s tu d i es fo r l o w .7 months although the details and site of extent of diseases are not available. with 25 μg autologous HSPPC-96 once a week for four weeks. One patient with advanced hepatocellular carcinoma was found to have extensive tumour necrosis of over 50% of the primary tumour after the third injection with HSPPC-96. micros o mes . Opin. After each vaccination. Of these.
With exception to this patient. As of May 2000. The vaccination did not induce increased frequencies of CD8+ T-cells reacting with autologous monocytes. two patients 4 x 25 μg. which compares favourably to the other available therapies for this population of patients. Due to these encouraging clinical results. 25 and 100 μg per injection) . The vaccine was prepared successfully from 5/15 pancreatic cancer samples. one patient is in complete remission. allowing for easy purification of HSPPC-96. those patients who exhibited disease progression continued with vaccine every two weeks.5. one patient 8 x 25 μg and one patient 9 x 100 μg HSPPC-96. Ther. 25 or 100 μg of HSPPC-96. Since this study is not yet complete. The fourth patient is alive with recurrent disease at 10 months and the fifth patient died seven months after starting HSPPC-96 treatment. including Hsps. Clinical activity has been demonstrated in 24% of patients for over 14 months. followed by two additional 25 μg doses at two week intervals. of whom 8 patients (32%) have continued on HSPPC-96 therapy alone.544 HSPPC-96: a personalised cancer vaccine anti-HCC CD8+ cell response. although there is no satisfactory treatment for this disease. Relapse-free survival and overall survival will be the sole objectives of this study. These two patients were treated in 1997 and are still alive and disease free in November 2000 (Lewis J. while the three of four patients remaining disease free were vaccinated with 25 μg and 100 μg vaccine doses. It was not possible to test higher dose levels due to the small size of tumours in these patients. A multi-institute worldwide randomised Phase III study was launched in the summer of 2000 to study the effect of autologous tumour-derived HSPPC-96 vaccination in stage III renal cell cancer patients who have undergone curative surgery. 6. showing the greater feasibility of vaccine preparation from resected gastric carcinoma than pancreatic cancer. HSPPC-96 was tested in a Phase I clinical trial for patients with pancreatic cancer . six patients received 4 x 2. spontaneous remission has been observed and a subset of patients can be cured with IL-2 and/or interferon. Biol. © Ashley Publications Ltd.2 Renal 6.5 μg. All rights reserved. All patients received four weekly 25 μg id. Patients who had primary. Responding or stable patients were continued with four additional doses of 25 μg at two week intervals. It was not possible to prepare HSPPC-96 from the remaining specimens due to the presence of proteolytic enzymes in the pancreatic tissue that break down proteins.5. A total of 70 patients have been enrolled in a Phase II trial . HSPPC-96 vaccination also did not lead to increased frequencies of patient CD8+ T-cells reactive with Exp. Five out of six patients with tumour progression were in the lowest vaccine dose level of 2. Moreover. As reported in October 2000 . A total of 38 patients were evaluable. 6.4 Gastric cancer Patients with a diagnosis of gastric carcinoma underwent gastric surgery with curative intent . plus a 5 day per week course of 11 million units of IL-2 delivered subcutanenously for four consecutive weeks. Four patients with tumour stages II and IIIa remain free of disease.5 μg. Opin. Tumour-specific T-cell mediated immune responses were demonstrated in two of the five patients. At least 1.5 months after surgery. The first Phase I renal cancer trial involved a total of 42 stage IV patients treated in three dosage groups (2. personal communication). one has had a partial response and six have stable disease. the pancreatic trial has now been expanded to treat more patients. it remains unclear whether combination of IL-2 with HSPPC-96 is effective for this population. no significant tumour lysis was observed in other patients. patients were vaccinated intradermally four to nine times in either weekly or two-week intervals with either 2.5 grams of resected tumour was procured from each patient and HSPPC-96 was purified. Vaccine preparation was successful in 12 out of 15 patients. resectable pancreatic cancer were enrolled in the trial. Full details in the Phase I trial have not yet been published. (2001) 1(3) . injections of HSPPC-96. After surgery to remove their primary tumour. Beginning four to eight weeks after surgery. A third patient was known to be free of disease at 12 months and was subsequently lost to follow-up. All five stage IIIb and IV patients and one stage IIIa patient developed tumour progression after a median of 6. 25 patients have completed the therapy. Of these eight. Other patients have progressive disease requiring addition of IL-2. These data suggest that HSPPC-96 is able to stimulate T-cell immunity even in patients with advanced stage malignancies.3 Pancreatic cancer cell carcinoma Renal cell cancer is a good model for immunological interventions involving the use of tumours because the primary tumour burden is often large and the initial diagnosis and treatment are radical nephrectomy. patients were treated with 5 μg of vaccine intradermally.
The gp96 molecule itself is among the most conserved molecules in these animals. With 9 month median follow-up. all lasting over seven months. Exp. The clinical development of this unprecedented vaccine has met with several unique challenges. therefore. Preclinical studies have shown that HSPPC-96 is broadly effective against a variety of tumours. gp96.. Eleven of the stage IV adjuvant patients (eight of whom were stage IVM1B) remained disease free a median of 11+ months. Opin. which requires new rules and regulations and new ways of thinking in order to measure the success of a biological therapy such as immunotherapy with HSPPC-96.5 Melanoma In a Phase I study. Patients showed no serious toxicities to therapy. 26 were graded stage IV and 10 were graded stage III. The hope. Previous in vitro data have shown that HSP70 purified from human melanoma cells was able to induce MHC class I-restricted antimelan o m a CTL activity when p r es ented to MHC-restricted APCs. 19 patients remain on study with 29 (80%) alive.). The manufacturing of HSPPC-96 is highly reproducible. Nevertheless. Hellman S. How. HSPPC-96 is made from a patient’s own cancer and is generally not in itself cytotoxic. However. TRICHOPOULOS D. In vitro studies to assess antitumour immunity elicited by HSPPC-96 vaccination in these patients are ongoing.5. In: Cancer Principles and Practice of Oncology (Edition 5). can immunological competence of the patient be ensured? How much immunosuppression is ‘safe’ and at what level does it become prohibitive for active immunisation with HSPPC-96? These questions await further research. without a proper surrogate marker. the principles learned in rodents about the immunological features of gp96 are so far holding firmly in other animals ranging from xenopus to humans . Patients were given id. The underlying mechanism is to stimulate antitumour immune responses against the tumour-specific peptides chaperoned by the ubiquitous Hsp. since HSPPC-96 itself is not directly cytotoxic. 6. such as chemotherapy and radiation therapy? Both chemotherapeutic agents and radiation are known to cause bone marrow suppression. PETRIDOU E. Of these patients. 25 or 100 μg weekly for four weeks. such as complement. Fourth.Caudill & Li 545 certain defined tumour peptide antigens from CEA. Ther. what are the best © Ashley Publications Ltd. how can immunotherapy with HSPPC-96 be incorporated into existing cancer strategies. Finally. then. J B Lipincott-Raven. surrogate immunological markers to determine successful HSPPC-96 immunisation ? There are no answers to this question. First. HSPPC-96 was purified in sufficient quantities for vaccination from samples weighing as little as 2 mg. 7. as the functions of APCs and NK cell components are also important for the therapeutic effect of HSPPC-96. p53 or HeR2/neu. vaccination at doses of 2. It is therefore certain that HSPPC-96 will find a way into the list of emerging arsenals in the fight against human malignancy . Second. an increase of NK-like cytotoxicity could be observed in two of the four patients with no evidence of disease. offering supportive evidence for a potential in vivo CTL response . one patient at each dose level had stabilisation or mixed response after initial progression in nodal or lung metastases. Being distinct from the traditional chemotherapeutic agents. 30 patients had had prior systemic therapy and 16 had indicator lesions. LIPWORTH L. As of April 2000. how should the clinical response with HSPPC-96 vaccination be evaluated? It is clear from animal studies and many of the ongoing clinical trials that the immune responses stimulated by HSPPC-96 are blunting tumour growth but tumours do not generally melt away. phagocytic cells and systemic or local cytokines? To summarise. or B-cell responses? What are the roles of other components. DeVita VT Jr. 36 patients were enrolled after resection of a > 3cm melanoma metastasis . Expert opinion HSPPC-96 is truly a personalised tumour vaccine. Clearly. (2001) 1(3) . Clonal expansions of CD8+ T-cells taken from patients during vaccination are currently being analysed by T-cell receptor (TCR)-Vβ-spectrotyping. What are the contributions of antibody. This also needs to be better defined. the efficacy of HSPPC-96 can only be judged by clinical response. measuring antitumour T-cell response is not enough. predictable and can eventually be automated. can personalised vaccine be reliably produced and delivered? The answer to this question is certainly yes. is to convert cancer into a manageable chronic disease. Rosenberg SA (Eds. Biol. All rights reserved. Bibliography Papers of special note have been highlighted as: • of interest •• of considerable interest 1. ADAMI H-O: Epidemiology of cancer. Philadelphia (1997):231-258.
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