The Hematologist

November-December 2018, Volume 15, Issue 6

Can We Vaccinate Our Way Out of Multiple Myeloma Progression?

Sabrin Tahri, MD Postdoctoral Research Fellow
Dana-Farber Cancer Institute, Boston, MA
Tarek H. Mouhieddine, MD Postdoctoral Research Fellow, Department of Medical Oncology
Dana-Farber Cancer Institute, Boston, MA
Irene M. Ghobrial, MD Associate Professor of Medicine
Harvard Medical School; Dana Farber Cancer Institute, Boston, MA

Published on: October 10, 2018

Nooka AK, Wang ML, Yee AJ, et al. Assessment of safety and immunogenicity of of PVX-410 vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial. JAMA Oncol. 2018;doi: 10.1001/jamaoncol.2018.3267. [Epub ahead of print].

The fundamental idea that the immune system has antitumor potential can be traced back to 1893 when Dr. William B. Coley reported on 10 sarcoma cases treated with injections of killed cultures of Streptococci and Bacillus prodigiosus producing erysipelas infection and inducing immune-mediated tumor regression.1 More recently, the therapeutic potential of the immune system has been appreciated due to the curative impact of allogeneic hematopoietic stem cell transplantation, such as the graft-versus–multiple myeloma (MM) effect.2 Profound immune dysfunction in MM has been demonstrated,3 therefore it is of no surprise that therapy targeting the suppressive tumor immune microenvironment has gained a lot of attention. Antitumor vaccination aims to overcome inadequate endogenous cellular antimyeloma immunity by stimulating effector cells to target myeloma cells. While early vaccine therapy studies were shown to be safe with minimal toxicity and to induce immunogenicity, clinical efficacy has been uncertain or limited.4,5 Critical issues to address in myeloma vaccine therapy include low mutational burden that results in lower numbers of neoantigen epitopes, unique fusion protein targets generated by chromosomal translocations, and the potential emergence of clonal populations with decreased immunogenicity upon immune editing of malignant clones.3

Dr. David Avigan and colleagues3 recently discussed key hurdles to overcome for finding a successful and effective antitumor vaccine. In addition to finding the optimal antigenic target for MM, alternative vaccine platforms are necessary to overcome the functional and phenotypical deficient endogenous antigen–presenting cell in the tumor immune microenvironment. Determining the appropriate setting for vaccination to maximize T-cell activation and prevent exhaustion and defining optimal combination therapies to augment the vaccine’s effect are essential in developing clinically significant antimyeloma vaccines. Furthermore, early immunotherapeutic interventions in smoldering MM (SMM) are attractive, not only because the rate of progression to MM is substantially greater versus monoclonal gammopathy of undetermined significance, but also because disease progression is associated with loss of myeloma-reactive clones in the T-cell repertoire, thereby limiting the immune response. This is analogous to what was observed in myeloid malignancies where clinical response of a peptide-based vaccine was predominantly noted in patients with low disease burden (<10% blasts in the marrow).6

To address the feasibility of vaccine therapy in a stage of limited disease-related immune suppression, Dr. Ajay K. Nooka and colleagues conducted a phase I/IIa nonrandomized clinical trial assessing the PVX-410 multipeptide vaccine in SMM. Twenty-two patients with HLA2-positive moderate- to high-risk SMM were assigned to one of three treatment cohorts, consisting of low-dose monotherapy (n=3), target dose monotherapy (n=9), or combination therapy (n=9) that consisted of biweekly subcutaneous vaccine injection along with three 21-day cycles of 25 mg oral lenalidomide. PVX-410 is an HLA2-restricted multipeptide vaccine composed of four chemically synthesized peptides from unique regions of three MM-associated antigens: X-box binding protein 1 (XBP1), CD138, and SLAMF7. These antigens were chosen based on in vitro data showing that each peptide individually stimulated antigen-specific cytotoxic T-lymphocytes resulting in cell proliferation, interferon-γ (IFN-γ) secretion, and cytotoxic activity in response to MM cells.7

Both PVX-410 monotherapy and combination therapy were well tolerated, with only grade 1 or 2 vaccine-related treatment-emergent adverse events such as chills, fatigue, myalgia and pyrexia, and injection-site reactions. No patients experienced a PVX-410-related serious adverse event or discontinued treatment because of a treatment-emergent adverse event. PVX-410 induced an immune response in 19 of 20 evaluable patients (10 of 11 monotherapy vs. 9 of 9 combination therapy) as measured by the increase in percentage of tetramer-positive CD3+CD8+ cells (1.5-fold increase) and IFN-γ cells (twofold increase). Antigen-specific T-cell response was measured at baseline and at weeks 4 and 8 post-treatment. The addition of lenalidomide increased the immune response magnitude at week 2 for IFN-γ, interleukin-2, and tumor necrosis factor α, and at week 4 for interleukin-2 and tumor necrosis factor α. Both therapies significantly increased effector memory CD8+ T cells, suggesting durable immune responses. Monotherapy resulted in stable disease (SD) with five of 12 patients progressing within 12 months, while combination therapy led to a partial response in one patient, minimal response in four patients, and SD in four patients. Those who did not progress had a greater immune response; specifically, patients showing more than tenfold response at more than two time points were more likely to demonstrate a clinical response or SD.

Although clinical response was modest, the safety, tolerability, and efficacy of the PVX-410 vaccine in SMM look promising. The complex nature of immune dysfunction and the low mutational burden in SMM supports the use of combination therapy. Lenalidomide induces antimyeloma immunity and potentiates vaccine therapy in MM,8,9 and it therefore seems a logical choice for combination therapy. Moreover, other strategies to potentiate antitumor vaccination are currently being studied by adding hypomethylating agents (NCT02886065), targeting earlier disease stages (NCT03591614), and developing a personalized “neoantigen” vaccine (NCT03631043). Could the answer be as simple as a vaccine to prevent progression to MM? There are still roadblocks to a cure for myeloma; however, focusing on treating precursor states and the promising developments in the field of immunology may be the perfect combination for evoking a potent immune response strong enough to reverse tumor-associated tolerance, arm the host immunity with an effective effector cell population to recognize myeloma cells, and induce lifelong memory against them.

References

  1. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991;3-11.
  2. Krishnan A, Pasquini MC, Logan B, et al. Autologous haematopoietic stem-cell transplantation followed by allogeneic or autologous haematopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195-1203.
  3. Avigan D, Rosenblatt J. Vaccine therapy in hematologic malignancies. Blood. 2018;131:2640-2650.
  4. Nahas MR, Rosenblatt J, Lazarus HM, et al. Anti-cancer vaccine therapy for hematologic malignancies: An evolving era. Blood Rev. 2018;32:312-325.
  5. Guo C, Manjili MH, Subjeck JR, et al. Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res. 2013;119:421-475.
  6. Qazilbash MH, Wieder E, Thall PF, et al. PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies. Leukemia. 2017;31:697-704.
  7. Bae J, Prabhala R, Voskertchian A, et al. A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia. 2015;29:218-229.
  8. Luptakova K, Rosenblatt J, Glotzbecker B, et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother. 2013;62:39-49.
  9. Sakamaki I, Kwak LW, Cha SC, et al. Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas. Leukemia. 2014;28:329-337.

Conflict of Interests

Dr. Tahri and Mouhieddine indicated no relevant conflicts of interest. Dr. Ghobrial has a consulting/advisory role with Celgene, Takeda, Bristol-Myers Squibb (BMS), Janssen Pharmaceuticals, and Amgen. She has received research funding/honoraria from Celgene, Takeda, Bristol-Myers Squibb (BMS), Janssen Pharmaceuticals, and Amgen. back to top