Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol.

Abstract

BACKGROUND:

There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial.

METHODS:

These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow.

DISCUSSION:

This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010.

• Authors: Sheeba K Thomas, Soung-Chul Cha, D Lynne Smith, Kun Hwa Kim, Sapna R Parshottam, Sheetal Rao, Michael Popescu, Vincent Y Lee, Sattva S Neelapu, Larry W Kwak
• Journal: BMC cancer (BMC Cancer) Vol. 18 Issue 1 Pg. 187 (02 13 2018) ISSN: 1471-2407 [Electronic] England
• PMID: 29439670 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens
• Chemokine CCL20
• Recombinant Fusion Proteins
• Vaccines, DNA

Topics

• Adult
• Aged
• Antigens (genetics, immunology, metabolism)
• Chemokine CCL20 (genetics, immunology, metabolism)
• Female
• Humans
• Immunotherapy, Active (methods)
• Male
• Middle Aged
• Outcome Assessment, Health Care
• Prospective Studies
• Recombinant Fusion Proteins (immunology, therapeutic use)
• Vaccination (methods)
• Vaccines, DNA (immunology, therapeutic use)
• Waldenstrom Macroglobulinemia (immunology, pathology, therapy)