Embed Size (px)
Citation preview
induced by an experimental tumour vaccine alone.
Geert Kersten, CEO of CEL-SCI, said:‘The fact that we were able to see protection without disease antigen inseveral diseases opens up the possibilitythat derG could become an inexpensivegeneral immune regulatory drug thatprotects people from a large number ofdiseases.’ Zimmerman added, ‘We didnot receive any reports of any adverseside effects [in the animals], such asweight loss or gain, diarrhoea, consti-pation, coat loss or discoloration, or evidence of neurological effects fromany of the three study sites.’
Further treatmentsPotential future indications for derG couldbe protection against other infectious dis-eases and a treatment for influenza, he-patitis B and C, and allergies. It could alsohave the potential to enhance protectiveimmunity following vaccination and couldeliminate the necessity of booster shots.
Zimmerman added that the next steps are: (1) to optimize for dose; (2) to evaluate in other strains and species forpreventive and therapeutic efficacy withappropriate disease models; and (3)large scale ADME/tox studies. He envis-aged the peptide going into clinical trials within two to three years.
References1 Charoenvit, Y. et al. (2002) A non-
immunogenic small peptide analogue of
human MHC II β chain induces protective
responses to tumor and infectious challenges.
Presented at the Experimental Biology 2002
meeting, 20–24 April 2002, New Orleans, LA,
USA (Poster LB517)
2 Cumming, J.N. et al. (1997) Antimalarial
activity of artemisinin (qinghaosu) and
related trioxanes: mechanism(s) of action.
Adv. Pharmacol. 37, 253–297
3 Clark, I.A. et al. (1976) Protection of mice
against Babesia and Plasmodium with BCG.
Nature 259, 309–311
4 Puri, S.K. et al. (1996) Poly ICLC inhibits
Plasmodium cynomolgi B malaria infection in
rhesus monkeys. J. Interferon Cytokine Res. 16,
49–52
DDT Vol. 7, No. 13 July 2002 updatenews
1359-6446/02/$ – see front matter ©2002 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(02)02351-6 693www.drugdiscoverytoday.com
Tailoring vaccines to individual lymphomasMatt Brown, [email protected]
A custom-made vaccine has been developed to combat non-Hodgkin’s lymphoma (NHL) that uses a patient’sown tumour cells. Researchers at theUniversity of Maryland GreenebaumCancer Center (Baltimore, MD, USA) aretesting the vaccine as part of a Phase IIImulti-centre study at 25 institutionsacross North America. The vaccine isparticularly targeted at follicular lymph-oma, a common and low-grade form of NHL.
Lymphomas: types and treatmentsNon-Hodgkin’s lymphoma is a term thatencompasses a wide variety of diseases.Lymphomas are cancers of the lymphaticsystem, which filters the blood and pro-tects the body from illness. As the cancergrows, the body accumulates large num-bers of non-functioning lymphocytes,which can block and compromise thelymphatic system and rapidly metasta-size to other organs. There are two
general types of lymphoma: Hodgkin’s(named after Thomas Hodgkin, who wasthe first to recognize this form in 1832)and non-Hodgkin’s lymphoma. NHL is much more heterologous, less pre-dictable and can attack more types oflymphatic tissue than Hodgkin’s lym-phoma can (for a background to the dis-ease see http://www.patientcenters.com/lymphoma/).
One particularly common but lower-risk type of NHL is follicular lymphoma.This disease afflicts mainly middle-agedand elderly people and can readilyspread to different parts of the lymphaticsystem. Most cases are the result of overexpression of the BCL-2 gene, whichproduces a protein that blocks apop-tosis. Current therapies for the diseasedepend on the extent of the cancer’sprogress. If the lymphoma is caughtearly, it can be treated with localized radiotherapy. Treatment is often deferred,however, until symptoms appear. When
the disease is more advanced, chemo-therapy or whole-body radiation mightbe necessary. Generally, low-grade follic-ular cancers are easily treated, but areprone to recur.
A tailor-made vaccineA team led by Aaron Rapoport atthe University of Maryland hasdeveloped a vaccine methodto combat follicular lym-phoma using an agent totarget a tumour-specificsurface protein called anidiotype, which is uniqueto every lymphomapatient. The vaccineis developed by conjugating theidiotype proteinto an immuno-genic carrierprotein, key-hole limpet
haemocyanin, which is potently capableof eliciting an immune response. Onceinjected, the vaccine prompts the im-mune system to attack only cells thatcarry the idiotype, that is, the cancercells. ‘Without this, the body’s immunesystem is somewhat blind to the lym-phoma. Lymphomas and other types ofcancers use mechanisms to evade thebody’s immune system’, said Rapoport.The work builds on earlier studies byRonald Levy at Stamford University [1].
In early clinical trials, about two-thirdsof patients showed positive immunologi-cal responses to the vaccine [2]. But the time and expense necessary to create each personalized immunother-apy limited its development. GenitopeCorporation (Redwood City, CA, USA)has overcome this limitation through itsproprietary high-throughput gene ex-pression technology. A Phase III clinicaltrial is now under way and hopes to at-tract 480 patients across the USA. Thesepatients must be over 18, not pregnantor lactating, have been diagnosed withfollicular cancer and should not havepreviously received chemotherapy.
Patients enrolled in the study have asmall biopsy taken from their tumour, either from a lymph node or bone marrow. The tissue is sent to Genitope(the sponsors of this research), wherethe tumour-specific genetic material is isolated, expressed and purified into
a vaccine-like immunotherapy. Mean-while, patients receive eight rounds ofchemotherapy with the drugs cytoxan,vincristine and prednisone. They mustexperience at least 50% reduction in tumour burden to remain in the study.
After a 26-week rest period followingchemotherapy (allowing the immunesystem to recover), two-thirds of patientssubcutaneously receive the specificallytailored vaccine, along with a proven im-mune system stimulant – granulocyte-macrophage colony-stimulating factor –that acts as an adjuvant [3]. The remain-ing third receive injections comprisingonly the carrier protein and the stimu-lant, which could also beneficially acti-vate the immune system. The patientsreceive a series of seven vaccinationsover six months, followed by periodicscans to check on the progress of thedisease. ‘I believe this technology offersthe potential for better treatment resultsthan we have previously seen’, concludedRapoport. This is the first demonstrationthat a personalized immunotherapy,when used as the initial treatment forpatients with follicular NHL, can inducetumour-specific immune responses.
The research complements similar trials that are currently taking placearound the world. Freda Stevenson ofSouthampton University (Southampton,UK) was one of the pioneers of this approach, generating immunity to
lymphoma in animals [4]. ‘The Rapoporttrial is a Phase III study, so it will be interesting to see what happens’, she commented. ‘However, it remains a difficult and tedious vaccine prepa-ration.’
A spokesperson from Genitope Corpo-ration maintains that the manufacturingand technological enhancements usedto develop the vaccines in the Phase IIIstudy are expected to overcome previ-ous limitations, which have inhibitedcommercial viability of these treatmentsin the past. The company hopes to com-plete the study by early next year.
References1 Timmerman, J. and Levy, R. (2000) The
history of the development of vaccines forthe treatment of lymphoma. Clin. Lymphoma1, 129–139
2 Timmerman, J. et al. (2000) A Phase II trial toevaluate the efficacy of recombinant idiotypevaccines in untreated follicular non-Hodgkin’s lymphoma in the ‘watch and wait’ period. American Society of ClinicalOncology 38th Annual Meeting, 18–21 May2002, Orlando, FL, USA, Abstract 13(available online at http://www.asco.org/cgi-bin/prof/abst.pl?absno=13&div=0059&year=02abstracts)
3 Simon, R.M. et al. (2001) Clinical trialdesigns for the early clinical development oftherapeutic cancer vaccines. J. Clin. Oncol.19, 1848–1854
4 Stevenson, G.T. and Stevenson, F.K. (1983)Treatment of lymphoid tumors with anti-idiotype antibodies. Springer Semin.Immunopathol. 6, 99–115
update news DDT Vol. 7, No. 13 July 2002
694 www.drugdiscoverytoday.com
Contributions to Monitor
We welcome recommendations of papers for review within Monitor, in the fields of combinatorial chemistry, pharmacogenomics,
pharmacoproteomics, bioinformatics, new therapeutic targets, high throughput screening, new drug delivery technologies
and other promising lines of research.
Details of recent papers or those in press should be directed to Dr Debbie Tranter, Editor, Drug Discovery Today,
Elsevier Science London, 84 Theobald’s Road, London, UK WC1X 8RR. tel: +44 207 611 4132, fax: +44 207 611 4485,
e-mail: [email protected]
