(New York, February 5th) — What if we could prevent cancer recurrence for years after surgery by giving simple recall injections every two or three years? This concept may no longer be a fantasy. In a clinical study published online this week by the Proceedings of the National Academy of Sciences USA, a team headed by the international Ludwig Institute for Cancer Research (LICR) has shown that a vaccine against a protein found in cancer cells produces an immune response that can be boosted and strengthened with additional vaccine shots. Patients with resected non-small cell lung cancer (NSCLC) were treated with this investigational agent, also known as an Antigen-Specific Cancer Immunotherapeutic (ASCI), in another clinical study conducted by GlaxoSmithKline. The results showed a reduction in risk of cancer recurrence in these patients, a finding that prompted GlaxoSmithKline to initiate the largest ever clinical trial in lung cancer (MAGRIT study).

According to LICR’s Dr. Sacha Gnjatic, the senior author of this LICR-sponsored study, the long ‘immunological memory’ is exactly what cancer immunologists are hoping to see. “Vaccines against infectious diseases induce immunological responses that typically last for years, and ideally we want a cancer vaccine that does the same thing. We previously learned that our vaccine could stimulate an immune response recognizing a protein found in lung cancer cells but we did not know how long the response lasted. We now know that this vaccine induces strong and persistent immunity over several years, which can be further ‘boosted’ with additional vaccination.” Dr. Gnjatic said that the booster shots, given two years after the first cycle of vaccinations, not only reactivated the initial immune response in patients who received the priming vaccination, it also diversified the types of immune cells specific for the cancer protein. “We’ve not only kept the immune system interested, we’ve also got it to more broadly recognize the protein that marks the cell as being a cancer cell.”

LICR and the Cancer Research Institute, both head-quartered in New York, supported the study under the auspices of the Cancer Vaccine Collaborative, with the clinical component conducted by Dr. Nasser Altorki at New York Presbyterian Hospital / Weill Medical College of Cornell University.

Cancer vaccines have two principal components. One component, the ‘adjuvant,’ stimulates the immune system in a general way, and the other component, the ‘tumor antigen’ — in this case, the MAGE-A3 antigen — directs the immune response specifically against the cancer cell. Last month, another LICR-sponsored clinical trial within the Cancer Vaccine Collaborative showed that a cancer vaccine based on the tumor antigen NY-ESO-1 stimulated an immune response in women with ovarian cancer. The results from that trial were suggestive that a similar boost strategy could be beneficial for long-term immunological memory in that disease also.

A completely unexpected finding from the present study was that the inital formulation and delivery of the tumor antigen to the immune system is critical and suggests that the combination of the antigen with an immunological adjuvant is key. The original, small clinical study, conducted three years ago by the Cancer Vaccine Collaborative, showed that the adjuvant was necessary for activation of the immune system; patients who received antigen alone failed to mount specific immune responses. Surprisingly, these same patients also failed to mount immune responses even when they received the full vaccine — adjuvant plus antigen — as a booster shot.

“This is such a surprising result,” says LICR’s Dr. Lloyd Old, another author on the study and Director of the Cancer Vaccine Collaborative. “In the vaccine field, boosters are given to convert negative or weak reactions to positive ones, and we really thought we would see the same thing. One intriguing possibility is that regulatory mechanisms were activated following the original weak response induced by the vaccine without adjuvant. These findings will certainly have ramifications for the whole field to determine the formulation and delivery of future cancer vaccines.”

1: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1650-5. Epub 2008 Jan 23. Links

 

Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming.

Atanackovic D, Altorki NK, Cao Y, Ritter E, Ferrara CA, Ritter G, Hoffman EW, Bokemeyer C, Old LJ, Gnjatic S.

Department of Oncology/Hematology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

We previously reported results of a phase II trial in which recombinant MAGE-A3 protein was administered with or without adjuvant AS02B to 18 non-small-cell lung cancer (NSCLC) patients after tumor resection. We found that the presence of adjuvant was essential for the development of humoral and cellular responses against selected MAGE-A3 epitopes. In our current study, 14 patients that still had no evidence of disease up to 3 years after vaccination with MAGE-A3 protein with or without adjuvant received an additional four doses of MAGE-A3 protein with adjuvant AS02B. After just one boost injection, six of seven patients originally vaccinated with MAGE-A3 protein plus adjuvant reached again their peak antibody titers against MAGE-A3 attained during the first vaccination. All seven patients subsequently developed even stronger antibody responses. Furthermore, booster vaccination widened the spectrum of CD4(+) and CD8(+) T cells against various new and known MAGE-A3 epitopes. In contrast, only two of seven patients originally vaccinated with MAGE-A3 protein alone developed high-titer antibodies to MAGE-A3, and all these patients showed very limited CD4(+) and no CD8(+) T cell reactivity, despite now receiving antigen in the presence of adjuvant. Our results underscore the importance of appropriate antigen priming using an adjuvant for generating persistent B and T cell memory and allowing typical booster responses with reimmunization. In contrast, absence of adjuvant at priming compromises further immunization attempts. These data provide an immunological rationale for vaccine design in light of recently reported favorable clinical responses in NSCLC patients after vaccination with MAGE-A3 protein plus adjuvant AS02B.

PMID: 18216244 [PubMed - indexed for MEDLINE