Rather than posting everything at once, I’ll cover a topic or two for each post.
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Vaccines for neuroblastoma
The two talks at ASCO that touched upon the concept of vaccines were on cellular therapies by Lawrence Cooper from MD Anderson, and immunotherapies by Alice Yu from San Diego in the Education Session. They reviewed the “state of the art” for these therapies, but no specifics on current or upcoming trials.
Backing up a bit, it is impressive to see how much work has been done in this arena with a focus on neuroblastoma. Pubmed brings up 175 articles, 27 reviews, and 60 free full text articles on “vaccine AND neuroblastoma.” I wonder with such a proliferation of vaccine products that have been developed for neuroblastoma how they ever prioritize testing these vaccines in children. The other question is, if so much work has been done, why are we still waiting for an effective vaccine? At the end of this post, this question is addressed.
There are only 5 clinical trial results published for vaccines given to children with neuroblastoma. As expected, vaccines work ideally in those with no detectable disease, and better in first remission than subsequent remissions. There is a challenge though in interpreting the results of these trials because it is too early for them to report long follow-up. How do we know if it works if a child is in a first remission and stays in remission? How do we know if they would have stayed in remission anyway, without the vaccine? In these studies “surrogate” markers are recorded as evidence of vaccine activity but the relationship between persisting activity to permanent remission is unknown. A vaccine may generate a whopping initial immune response to the NB, but then fade quickly away. The only way to get a solid idea of the lasting effectiveness of a vaccine is to give it to several children in second remission and see how long they survive without relapsing again, or in a randomized trial just like the ch14.18 which showed better outcome in the group that got the ch14.18.
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Clinical trial results for vaccines in NB kids
In a phase I study published in 2007 by Heidi Russell at Texas Children’s, a vaccine was made from each child’s own tumor cells that were modified to secrete IL-2 and lymphotactin (a chemokine that attracts T cells). The vaccine was given to 7 patients with relapsed or refractory neuroblastoma. Results showed that the vaccine caused little toxicity and can induce an antitumor immune response, but the immune response was insufficient to overcome active recurrent neuroblastoma.[1] Heidi Russell’s subsequent study (phase I/II) published in 2008 also showed that a similar vaccine (without secretion of lymphotactin) was safe and antitumor immune responses were generated. Thirteen patients (8 in first remission and 5 after treatment for recurrent NB) received 5 to 8 subcutaneous injections. Median event-free survival was 22 months for patients in first remission and 3 months for all others. Three out of the 8 patients treated in first remission remained alive without disease recurrence (as of publication).[2]
An Australian phase I study published in 2005 used each child’s monocyte-derived dendritic cells (DC) pulsed with the child’s tumor RNA (from primary tumor surgery) to produce antitumor vaccines (DC(RNA)). This vaccine was given to 7 stage 4 children after frontline therapy with stem cell transplant. They were first given vaccines for tetanus and diphtheria to test immune response to these vaccines, and then given the NB vaccine multiple times (weekly, then monthly with a plan to give 6 total doses). This small study had four children with measurable disease after transplant, and 3 were in remission at the time the vaccines were given. None of the children got all 6 planned doses: 3 children received the vaccine 4 times and 3 children received the vaccine 3 times. The outcomes in the study were very poor and this should be interpreted carefully because with such small numbers, it could represent a small subset of very poor prognosis cases. All 11 enrolled had disease progression before 2 years, and only one was still alive at 14 months after diagnosis at the time of the paper was written. The authors concluded the children were too immunodeficient after transplant to mount an immune reaction to the vaccine, based on the poor response detected from the tetanus and diphtheria vaccines given before the NB vaccine.[3]
In 2003 an interesting phase I study was published (from Baylor and St Judes). An allogeneic neuroblastoma vaccine was produced from a cell line established in 1979 from a patient with disseminated neuroblastoma. The cells were modified to secrete lymphotactin and IL-2. The vaccine was given to 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections in a dose-escalating scheme. The vaccine produced significant increases in the children’s T cells, NK cells, eosinophils, and IL-5. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient.[4]
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Difficulties and ideas
A recent article (2009) in Blood explains some of the challenges to developing curative vaccines. Two issues are important for success: stimulating the immune system to mount a response to the tumor antigens and maintaining development of long-term tumor immunity (memory). The study in mice revealed the conflict of accomplishing both:
A multifaceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of sensitized T cells (from syngeneic donors vaccinated to tumor antigens), and early posttransplantation tumor vaccination can effectively treat mice with established neuroblastoma. Vaccination was an important component of this immunotherapy, as it resulted in enhanced and prolonged tumor-specific CD8 T-cell activity and improved antitumor efficacy. Surprisingly, CD4 cell depletion of mice given sensitized T cells resulted in better tumor-free survival, which was associated with an early increased expansion of CD8 T cells with an effector phenotype, increased numbers of tumor-reactive CD8 T cells, and increased tumor infiltration by CD8 T cells. However, in the absence of CD4 T cells, development of long-term tumor immunity (memory) was severely compromised as reflected by diminished CD8 T-cell recall responses and an inability to resist tumor rechallenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the ideal initial antitumor response but still preserve antitumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early antitumor immunity and induce a long-lasting tumor response after HSCT.[5]
And finally, an older paper published in 2000 with a depressing title “Failure of cancer vaccines: the significant limitations of this approach to immunotherapy” summarizes some of the challenges.
Subsets of neoplastically transformed cells have been shown to (re-)express on their surface molecules which are not typically present on the surface of neighboring normal cells. In some instances, especially in malignant melanomas, cytotoxic T lymphocytes (CTLs) directed against such tumor associated antigens (TAAs) have been isolated. The cancer vaccine approach to therapy is based on the notion that the immune system could possibly mount a rejection strength response against the neoplastically transformed cell conglomerate. However, due to the low immunogenicity of TAAs, downregulation of MHC molecules, the lack of adequate costimulatory molecule expression, secretion of immunoinhibitory cytokines, etc., such expectations are rarely fulfilled. Various approaches have been explored ranging from the use of irradiation inactivated whole-cell vaccines derived from both autologous and allogeneic tumors (even tumor cell lines), and genetically modified versions of such cellular vaccines which aim at correcting costimulatory dysfunction or altering the in situ humoral milieu to aid immune recognition and activation. Anti-idiotype vaccines, based on cancer cell associated idiotypes, have also been explored which aim at increasing immunogenicity through in vivo generation of vigorous immune responses. Dendritic cell (DC) vaccines seek to improve the presentation of TAAs to naive T lymphocytes. Unfortunately, there is always the possibility of faulty antigen presentation which could result in tolerance induction to the antigens contained within the vaccine, and subsequent rapid tumor progression. The theoretical basis for all of these approaches is very well founded. Animal models, albeit highly artificial, have yielded promising results. Clinical trials in humans, however, have been somewhat disappointing. Although general immune activation directed against the target antigens contained within the cancer vaccine has been documented in most cases, reduction in tumor load has not been frequently observed, and tumor progression and metastasis usually ensue, possibly following a slightly extended period of remission. The failure of cancer vaccines to fulfill their promise is due to the very relationship between host and tumor: through a natural selection process the host leads to the selective enrichment of clones of highly aggressive neoplastically transformed cells, which apparently are so dedifferentiated that they no longer express cancer cell specific molecules. Specific activation of the immune system in such cases only leads to lysis of the remaining cells expressing the particular TAAs in the context of the particular human leukocyte antigen (HLA) subclass and the necessary costimulatory molecules. The most dangerous clones of tumor cells however lack these features and thus the cancer vaccine is of little use. The use of cancer vaccines seems, at present, destined to remain limited to their employment as adjuvants to both traditional therapies and in the management of minimal residual disease following surgical resection of the primary cancer mass.[6]
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Current clinical trials and future promise
To summarize, the job is not done. As quote above, the theoretical basis is sound, and some of the animals studies produce astounding cures (see a recent study using poliovirus curing mice[7]), but the truth is that the tumor cell can be camouflaged so easily as “self” because the origin IS self. Vaccines against viruses and other evils originate elsewhere and that is why maintaining “immune memory” is so much easier.
Open trials are underway at:
Contact the principal investigator for the current status of the trial.
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References:
1. Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J Immunother. 2007 Feb-Mar;30(2):227-33.PMID: 17471169
2. A phase 1/2 study of autologous neuroblastoma tumor cells genetically modified to secrete IL-2 in patients with high-risk neuroblastoma. J Immunother. 2008 Nov-Dec;31(9):812-9.PMID: 18833006
3. Results of a Phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 neuroblastoma. Cancer. 2005 Mar 15;103(6):1280-91.PMID: (free fulltext) 15693021
4. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood. 2003 Mar 1;101(5):1718-26. Epub 2002 Oct 24.PMID: 12406881
5. Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory. Blood. 2009 Apr 30;113(18):4449-57. Epub 2009 Jan 30. (free fulltext) PMID: 19182203
6. Failure of cancer vaccines: the significant limitations of this approach to immunotherapy. Anticancer Res. 2000 Jul-Aug;20(4):2665-76. PMID: 10953341
7. Oncolytic treatment and cure of neuroblastoma by a novel attenuated poliovirus in a novel poliovirus-susceptible animal model. Cancer Research 67, 2857, March 15, 2007. PMID: 17363609
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