Disease relapse is the most common reason for treatment failure of both autologous (auto) and allogeneic (alio) blood and marrow transplantation (BMT). As such, there is the unmet need to augment antitumor immunity in these settings. We propose a novel adoptive cell therapy (ACT) approach to augment antitumor immunity after autoBMT and to treat the post-transplant relapse after alloBMT by exploiting the unique characteristic of the bone marrow as both the primary anatomic site for most hematologic malignancies and a compartment enriched with tumor-reactive marrow infiltrating lymphocytes (MILs). We hypothesize that ex vivo activated tumor-specific MILs can impart measurable and sustainable antitumor immunity upon adoptive transfer. This hypothesis is formulated on the basis of our preliminary data and by bringing together innovative strategies developed during the previous funding cycle. MILs from multiple myeloma patients can be expanded ex vivo with anti-CD3/CD28 stimulation and activated as to significantly Increase their tumor specificity in ACT studies. Similarly, MILs obtained from patients undergoing alloBMT using PTCy-based GVHD prophylaxis can also be expanded, using the same techniques and augment their antitumor reactivity. Accordingly, in Specific Aim #1, we will determine if activated MILs in combination with an allogeneic myeloma cell vaccine or lenalidomide can augment and/or sustain antitumor immunity after autoBMT and assess the impact of activated MILs on immune reconstitution, tumor-specific immunity and correlate these parameters with clinical responses.
In Specific Aim #2, we will conduct a phase l/ll clinical trial to evaluate the feasibility/safety of alloMILs obtained from the patient as a more tumor-specific "DLI" in patients with myeloid and lymphoid malignancies relapsing after alloBMT following PTCy and examine the impact of activated alloMILs on immune reconstitution, risk of GVHD, and tumor-specificity. Finally, in Specific Aim #3 we will characterize the effects of lenalidomide on modulating MILs'intrinsic differentiation program, expansion, survival, and extrinsic Inhibitory signals and determine the effects of coinhibitory molecules on the ability of MILs to augment antitumor immunity. In aggregate, the proposed research is significant in addressing an important unmet need of reducing or treating relapsed disease following BMT through clinical studies as well as increasing the overall understanding of mechanisms of antitumor immunity and developing innovative ACT strategies utilizing MILs to augment antitumor immunity posttransplant.

Public Health Relevance

The proposed work will evaluate the safety and efficacy of ACT with MILs in patients with advanced hematological malignancies undergoing auto or alloBMT. The relevance of this approach lies in the development of a highly innovative adoptive immunotherapy strategy that attempts to increase tumor-specific immunity after auto and alloBMT with potentially less alloreactivity and broad applicability for most hematologic malignancies. Furthermore, in contrast to several currently utilized ACT strategies, the simplicity of this approach makes it easily exportable to most institutions with experience in cell-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA015396-39
Application #
8727262
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
39
Fiscal Year
2014
Total Cost
$328,547
Indirect Cost
$125,740
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Kanakry, Christopher G; Fuchs, Ephraim J; Luznik, Leo (2016) Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol 13:132

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