Researchers Explore Novel Approaches to Boost Immunotherapy Vaccines

Immunotherapy vaccine approaches that involve harvesting a patient’s dendritic cells and priming them to recognize a tumor-specific antigen before injecting them back into the patient to activate a T-cell response against the tumor have achieved encouraging but limited success.

Immunotherapy vaccine approaches that involve harvesting a patient’s dendritic cells and priming them to recognize a tumor-specific antigen before injecting them back into the patient to activate a T-cell response against the tumor have achieved encouraging but limited success.¹For example, men with prostate cancer treated with the dendritic-based vaccine sipuleucel-T typically respond but eventually experience disease progression.¹Researchers have increasingly been looking at various ways to enhance the effectiveness of immunotherapy against different types of cancer.²

A US study jointly funded by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute found that administering a tetanus booster shot at the site where the dendritic-based vaccine was subsequently injected improved median overall survival in 12 patients with glioblastoma.^3,4Patients were randomly assigned to receive the tetanus booster followed by an injection of dendritic cells programmed with a cytomegalovirus antigen or to an injection of autologous nonprogrammed dendritic cells followed by an injection of the primed dendritic cells.

Investigators found a greater number of dendritic cells had migrated to the lymph nodes in patients who received the tetanus booster and the overall survival in this group was 36.6 months compared with 18.5 months for patients who did not receive the booster shot.^3,4One woman who received the treatment is alive after 9 years. Although the findings are promising, a much larger trial is needed to confirm the results.

The focus in immunotherapy vaccine research has expanded in recent years to include the use of modified T-cells. Guenther Koehne, MD, a medical oncologist and medical director of the Memorial Sloan Kettering Cancer Center’s (MSKCC’s) Cytotherapy Lab, is an investigator for a phase I trial evaluating T cells modified to target Wilms tumor antigen 1 (WT₁) in patients with multiple myeloma or plasma cell leukemia.⁵A video posted at the MSKCC website in April 2014 discusses the case of Ruth Lacey, the first patient Koehne treated with the WT₁-specific T cells.

Lacey had multiple myeloma that progressed to plasma cell leukemia after chemotherapy, and she had exhausted all standard treatment options. At Koehne’s recommendation, she underwent an allogeneic stem cell transplant. After the transplant, Lacey still had active disease. With the US Food and Drug Administration’s (FDA’s) consent, Koehne gave Lacey an infusion of WT₁-specific T cells harvested from the T lymphocytes of Lacey’s stem cell donor, cultivated in the laboratory, and pulsed with WT₁peptides, a protein overexpressed in various cancers, including multiple myeloma. The modified T cells bound to the WT₁protein as anticipated and eradicated the myeloma cells. After 2 additional WT₁-specific T-cell infusions, Lacey achieved a complete remission, which she maintained for more than 2 years before her disease relapsed.^6,7In the video, Koehne describes the new vaccine strategy as a “game changer.”⁶

In Koehne’s ongoing phase I trial, patients with multiple myeloma or plasma cell leukemia undergo an allograft transplant (human leukocyte antigen—matched or unmatched) and receive the first infusion of WT₁-specific T cells 6 to 10 weeks later. If the investigator considers it safe, the patient receives 2 more infusions of the WT₁-specific T cells. Koehne recently told the UK Daily Mail that 15 patients have been treated in the trial, all with a prognosis at enrollment of mere months and few treatment options.⁷He said half were still alive.⁷

The Daily Mail article notes that British researchers at the University College London and Royal Free Hospital are evaluating a similar immunotherapy approach in which T cells are harvested directly from patients with leukemia, exposed in the laboratory to particles carrying WT₁protein DNA, and re-infused into the patient.7 The US Army Medical Research and Materiel Command, MSKCC, and MD Anderson Cancer Center are collaborating on a phase II trial to determine whether or not the WT₁peptide vaccine can prevent the recurrence of mesothelioma, another cancer that expresses high levels of WT₁proteins.⁸The Seattle Cancer Care Alliance is also investigating different T-cell immunotherapy approaches in cancer and has several trials under way.^9,10

A vast amount of research is evaluating a plethora of immunotherapy approaches in oncology. Data on some of novel vaccine strategies will be presented at the 2nd Immunotherapy of Cancer Conference, being held from March 25-27, 2015, in Munich, Germany. The conference also includes a plenary session on immunotherapy vaccines.¹¹A CME conference sponsored by Physician’s Education Resource (PER) called Transforming Immuno-Oncology Across Solid Tumors, will take place in Chicago, IL on Friday May 29th, 2015.¹²

References

1. Bear AS, Cruz CR, Foster AE. T cells as vehicles for cancer vaccination.J Biomed Biotechnol. 2011;2011:417403.
2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.N Engl J Med. 2010;363:411-422.
3. National Institutes of Health. Strengthening the immune system's fight against brain cancer [press release]. http://www.nih.gov/news/health/mar2015/ninds-18.htm. Published March 18, 2015. Accessed March 24, 2015.
4. Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.Nature. 2015;519:366-369.
5. Memorial Sloan Kettering Cancer Center. Guenther Koehne, MD, PhD biography. http://www.mskcc.org/cancer-care/doctor/guenther-koehne. Accessed March 24, 2015.
6. Memorial Sloan Kettering Cancer Center. Case study: WT1-specific T-cell responses in a patient with plasma cell leukemia and relapsed refractory multiple myeloma. http://www.mskcc.org/videos/case-study-wt1-specific-t-cell-responses-patient-plasma-cell-leukemia-and-relapsed-refractory-multiple-myeloma. Published April 2014. Accessed March 24, 2015.
7. Adams S. Is this a miracle cancer vaccine? Scientists hail breakthrough treatment as a ‘game changer.’ http://www.dailymail.co.uk/health/article-3005816/Is-miracle-cancer-vaccine-Scientists-hail-breakthrough-treatment-game-changer.html#ixzz3VDo3tEFO. Published March 21, 2015. Accessed March 24, 2015.
8. ClinicalTrials.gov. Phase II study of adjuvant WT-1 analog peptide vaccine in MPM patients after MSK10-134. https://clinicaltrials.gov/show/NCT01890980. Updated March 16, 2015. Accessed March 24, 2015.
9. Seattle Cancer Care Alliance. T-cell therapies. http://www.seattlecca.org/diseases/immunotherapy-t-cell-therapies.cfm. Accessed March 24, 2015.
10. Bar M. Researchers aim to improve blood cancer outcomes with engineered T-cell treatments. http://www.onclive.com/publications/obtn/2013/december-2013/researchers-aim-to-improve-blood-cancer-outcomes-with-engineered-t-cell-treatments/1. Published January 2, 2014. Accessed March 24, 2015.
11. ITOC 2. 2nd Immunotherapy of cancer conference programme book. http://itoc-conference.eu/files/2014/05/ITOC2-Programme-book-FINAL-2.pdf. Accessed March 24, 2015.
12. Physician’s Education Resources. CME Conferences. http://www.gotoper.com/conferences/asco15/meetings/targeting-pathways-efficacy-and-combinations. Accessed March 24, 2015.