Maximum results may have already been achieved with conventional and high-dose chemotherapy for diseases such as acute myeloid leukemia, multiple myeloma and the lymphomas. The effectiveness of alternative agents such as Rituxan® and Gleevec® have amply demonstrated the efficacy of non-chemotherapy approaches to the treatment of hematologic malignancies. Another area which shows promise for contributing to the control of cancer is immunotherapy, especially cellular therapies and vaccines. At ASH 2003, there were a number of phase I and II studies of interest, which will probably lead to phase III studies in the near future.

Cellular Therapies

There have been many attempts in the past to expand lymphocytes ex vivo and infuse them in hopes of obtaining a specific or non-specific T-cell anti-tumor effect. The most well-known of these attempts was the use of IL-2 activated killer (LAK) cells for the treatment of melanoma and renal cell carcinoma in conjunction with systemic IL-2. Although possibly effective, this approach has been abandoned in favor of IL-2 alone, without the infusion of LAK cells.

One rationale for infusing lymphocytes after stem cell transplantation was presented in a poster session by researchers from the Mayo Clinic.¹ They reported that the day 15 absolute lymphocyte count after an autologous transplant was closely related to survival in an analysis of 267 patients. They also observed that the survival was improved in those patients who received more than the median dose of lymphocytes in the infused stem cell graft (median survival of 59 months) compared to 29 months for those who received a lower lymphocyte dose. Improved survival was also correlated with a faster recovery of peripheral blood lymphocytes.

Xcyte, a Seattle based biotech company, has developed an ex-vivo technique for producing expanded activated T-cells suitable for clinical use. Preliminary results of three clinical trials were presented at the 2003 ASH meeting. The specifics of generating activated T-cells by this technique were presented in a poster session.² This technique involves the expansion of T-cells, which are activated with anti-CD3 and anti-CD28 antibodies covalently linked to magnetic beads. Cultured T-cells are antigen specific and cytolytic. Researchers from Xcyte also presented data suggesting that the cell expansion process has been improved and is more efficient, allowing for large clinical trials with cells that meet all the FDA requirements.³

The feasibility of infusing in-vitro expanded T-cells to patients with multiple myeloma was presented by a multicenter group.⁴ Expanded T-cells were infused 3 days after an autograft. Thirty-five patients have been treated at Cedars-Sinai Medical Center, Hackensack University, Johns Hopkins University, University of California, San Francisco, and Washington University. Data on 28 of these patients were presented at the meeting. These authors reported an enhanced lymphocyte recovery compared to historical controls. There were apparently no associated toxicities. It is obviously difficult to evaluate responses in this type of study. Ultimately, a large randomized trial will have to be carried out to determine clinical benefit of this adjuvant type of immunotherapy.

A trial of Xcellerated T-cell™ infusions as the sole therapy for patients with chronic lymphocytic leukemia (CLL) was also presented.⁵ In the phase I/II clinical trial in CLL, 11 of 18 planned patients had been treated to date with a single infusion of increasing doses of Xcellerated T-cells™ without any other therapy at the University of California, San Diego, and The University of Texas M. D. Anderson Cancer Center. The investigators reported a 50% or greater reduction of enlarged lymph nodes and spleens in 10 out of 11 patients. Further follow-up will be required to determine the clinical significance of these results.

Researchers from Baylor University have treated 9 patients with EBV positive nasopharyngeal cancer with ex-vivo generated EBV specific cytotoxic T-cells.⁶ Four of the 9 patients treated were in CR at the time of immunization and none have relapsed. There were 2 PRs in patients with active disease.

In a phase I trial reported at ASH 2003, researchers from Rush University evaluated infusing allogeneic ex-vivo generated allogeneic natural killer cells.⁷ This was a dose-escalation trial to establish dose and safety, but at least 2 patients had a response and others experienced possible stabilization.

Vaccines

Most, if not all, vaccines for NHL are idiotype vaccines that are patients specific and require tumor obtained from individual patients which often limits this approach.

Dendritic Cell Based Vaccines

Italian researchers reported a phase I/II study of an anti-Id vaccination with dendritic cells.⁸ Dendritic cells were generated from peripheral blood monocytes, which were collected by CD34+ cell selection. All patients received tandem autografts followed by vaccination and dendritic cell infusions. This study showed the feasibility of vaccination and the infusion of primed dendritic cells. Patients developed T-cell reactivity to the vaccine and dendritic cells, but clinical effectiveness can probably only be determined in a randomized trial.

Researchers from Baylor University reported responses in metastatic melanoma in patients who had an immune response to a dendritic cell vaccine.⁹ This vaccine was derived from CD34+ peripheral blood cells that were pulsed with tyrosinase, MAGE-3, MART-1, and gp 100 peptides that are melanoma specific or melanoma associated antigens. The adjuvant was KLH. They immunized 17 evaluable patients. Six of seven patients who did not have specific immunity to 2 or less antigens had progression of melanoma. “In contrast, 9 out of 10 patients with immunity to greater than 2 melanoma antigens had measurable tumor regression or stable disease.” Five of the 18 patients in this study had a complete response to vaccine treatment alone. Two additional patients achieved a CR after additional vaccinations and surgery. At the end of the study, 5 patients were in CR and one was in PR.

Anti-idiotype Vaccines in NHL

MyVax™ is a personalized recombinant idiotype-KLH vaccine that is currently being evaluated in patients with low-grade NHL in a large randomized phase III clinical trial. The current study involved patients with mantle cell lymphoma who had received CHOP chemotherapy.¹⁰ Researchers from Cornell, the University of Nebraska, and Standford University administered MyVax™ to 27 patients with aggressive mantle cell lymphoma following CHOP therapy. The first group of 14 patients received 5 immunizations over 5 weeks, beginning 6 months after completing CHOP. The median time to progression in this group was 254 days. Subsequent patients were treated on an accelerated vaccination schedule beginning 3 months after CHOP and they appear to have a longer time to disease progression. Once the optimal schedule is developed, a phase III study will be needed to confirm efficacy.

Researchers from the NCI evaluated an idiotype vaccine in patients with untreated mantle cell lymphoma following induction with an EPOCH-Rituxan® regimen.¹¹ Vaccine was administered to 25 patients at least 12 weeks following completion of chemo-immunotherapy. The CR rate was over 90% to the induction regimen. Progression-free survival was approximately 20 months. Both cellular and humoral responses were elicited with the vaccine.

A multicenter clinical trial evaluated the single-agent activity of FavId™ (Favrille, Inc) for treatment of indolent lymphoma.¹² As with other idiotype vaccines, this one is also prepared from each patient’s tumor. The investigators reported that 32 patients had been treated and tumor regression was observed in 30% with one CR and 3 PRs. There were essentially no toxicities. The authors stated that “Utilizing cytoreductive therapy prior to FavId™ and enrolling less heavily pre-treated patients may improve the response rate.” These same researchers reported preliminary data of FavId™ immunization following Rituxan® treatment.¹³ They treated 19 previously untreated patients and 53 who had failed prior therapy. Twenty-one patients were evaluable for response. They reported that 5 patients who had achieved a PR with Rituxan® had continued tumor shrinkage and 2 patients with a minimal response to Rituxan® achieved a PR with vaccination. These were early data but do suggest that patients are responding to the vaccine. Researchers from the University of California, San Diego, reported immune responses in 6 patients who received the FavId™ following autologous stem cell transplantation for mantle cell or indolent lymphoma.¹⁴

Researchers from Germany reported the outcomes of 18 patients with advanced NHL treated with their idiotype vaccine.¹⁵ They reported significant T-cell responses and 2 complete responses, with possible prolongation of survival in others.

Heat-Shock Protein Vaccines

Heat shock proteins (HPS) are naturally occurring substances that bind all peptides they come in contact with. HPS are also capable of activating antigen presenting cells, indirectly presenting antigens, and “chaperoning” peptides during antigen presentation. Antigenics Inc. has developed a vaccine called HSPPC96. Individual tumor cells are mixed with HSP to create individual peptides which serve as tumor specific or tumor associated antigens. When re-injected into the patient from whom the cancer was obtained, specific immune responses are observed. This means that the vaccine contains all of the myriad of tumor antigens present in the cancer. Antigenics has developed a commercial system where tumors can be sent to the laboratory and a potentially commercially viable vaccine is returned to the physician. Researchers from MD Anderson reported on the safety and efficacy of HSPPC-96 in newly diagnosed patients with low grade NHL.¹⁶ They reported that 3 of the first 14 treated patients responded with 5 additional patients having stable disease. There were no significant side effects and the plan is to evaluate this vaccine in patients with minimal residual disease.

Conclusion

In summary, there appears to be some progress in the development of vaccines and cellular therapies for patients with NHL and multiple myeloma. All of these strategies will require large randomized trials in patients with minimal residual disease to show effectiveness. The best setting for the testing of cellular therapies and vaccines is probably following an autologous stem cell transplantat where disease burden is low and the immune system has been restored.

References

1. Porrata LF, Gertz MA, Litzow MR, et al. The Dose of Infused Lymphocytes Correlates with Clinical Outcome after Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation in Multiple Myeloma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:988a, abstract number 3678.

2. Long SA, Kalamasz D, Tanaguchi R, et al. Modulating T Cell Signals using Xcyte™ Dynabeads® Leads to Selective Expansion of Antigen-Specific T Cells. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:55b, abstract number 3922.

3. Hami LS, Harjinder C, Wood T, et al. Comparability of Xcellerated T Cells™ Manufactured Using a Static Culture Process and a Bioreactor Process for the Treatment of Patients with Multiple Myeloma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:964a, abstract number 3592.

4. Ravi V, Borrello IM, Martin T, et al. A Phase I/II study of Xcellerated T Cells™ after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:43a, abstract number 139.

5. Kipps TJ, Castro JE, Wierda W, et al. A Phase I/II Trial of Xcellerated T Cells™ in Patients with Chronic Lymphocytic Leukemia (CLL). Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:109a, abstract number 370.

6. Straathof KC, Bollard CM, Popat UR, et al. Cytotoxic T Lymphocyte Therapy for Epstein Barr Virus-Positive Nasopharyngeal Carcinoma. Patient specific T-cell were immunized with EBV postitive cells. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:125a, abstract number 426.

7. Arai S, Kindy K, Swearingen M, et al. Phase I Study of Adoptive Immunotherapy Using the Cytotoxic Natural Killer (NK) Cell Line, NK-92, for Treatment of Advanced Renal Cell Carcinoma and Malignant Melanoma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:693a, abstract number 2566.

8. Curti A, Cellini C, Terragna C, et al. Phase I-II Trial of Anti-Cancer Vaccination for Multiple Myeloma Patients Using Dendritic Cells Pulsed with Tumor Idiotype (Id) or Id (VDJ)-Derived Peptides. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:686a, abstract number 2539.

9. Fay JW, Paluka K, Paczesny S, et al. Regression of Metastatic Melanoma by Dendritic Cell-Induced T-Cell Immunity. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:124a, abstract number 425.

10. Leonard JP, Vose J, Timmerman J, et al. Recombinant Idiotype-KLH Vaccination (MyVax™) Following CHOP chemotherapy in Mantle Cell Lymphoma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:105a, abstract number 357.

11. Wilson WH, Neelapu S, Rosenwald A, et al. Idiotype Vaccine and Dose-Adjusted EPOCH-Retuximab Treatment in Untreated Mantle Cell Lymphoma: Preliminary Report on Clinical Outcome and Analysis of Immune Response. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:105a, abstract number 358.

12. Redfern C, Guthrie TH, Adler M, et al. Single Agent Activity of FavId™ (Id-KLH vaccine) for Indolent NHL.. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:898a, abstract number 3341.

13. Gold D, Redfern C. Woermol PH, et al. FavId™ (Id-KLH vaccine) Following rituximab for Patients with Indolent NHL. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:899a, abstract number 3347.

14. Holman P, Medina B, Corringham S, et al. Early and Robust Immune Responses to Idiotype (Id) Vaccination Occur in Mantle Cell Lymphoma (MCL) and Indolent Lymphoma (IL) Following Autologous Stem Cell Transplantation. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:899a, abstract number 3345.

15. Veelken H, Mauerer K, Mikesch K, et al. Immune Responses and Clinical Outcomes of Patients with Advanced Non-Hodgkin’s Lymphoma after Immunization with a Novel Recombinant Idiotype Vaccine. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:898a, abstract number 3342.

16. Younes A, Fayad L, Pro B, et al. Safety and Efficacy of Heat Shock Protein-Peptide 96 Complex (HSPPC-96) Vaccine Therapy in Patients with Relapsed or Previously Untreated Low-Grade Non-Hodgkin’s Lymphoma. Proceedings of the 45th annual meeting of the American Society of Hematology. Blood 2003;102:898a, abstract number 3343.