Collaborating Investigator: Dr. Ivan Borrello
Affiliation: Associate Professor of Oncology, Johns Hopkins University School of Medicine

Funding Source: Regional oncology research center
Grant Number: NIH P30CA006973
Project Period: 05/01/17-04/30/22
Project Status: New

Significance

In multiple myeloma (and many other heme- and non heme malignancies), the bone marrow is enriched for cancer specific T cells. Moreover, the higher efficiency of antigen presentation and greater concentration of central memory T cells in the marrow, make MILs a unique type of cells for adoptive T cells therapy. MILs technology expands and activates these cells ex vivo and then re-infuses them in the patient. In TRD 4 we seek to metabolically reprogram cells to enhance their efficacy and persistence. Collaborating with Dr. Borrello’s group affords us an extraordinary opportunity to test this hypothesis in an ongoing clinical program of Adoptive Cellular Therapy for Cancer. In this regard, our findings are readily translatable. With this collaborative project we hope to not only further Adoptive Cellular Therapy but also develop a tool box for metabolic reprogramming that can be exploited for not only enhancing immunotherapy for cancer but for a vast array of immunologically engineered systems.

Approach

Using metabolically defined media or JHU3202-01 to enhance memory generation in Adoptive Cellular Therapy for Cancer:
The Borrello lab has established a functional assay in NOD/SCID mice to evaluate the efficacy of the MILs. In this assay NOD/SCID mice are given 200 rads of XRT on day 0 then injected with 5 million H929 human multiple myeloma cells on day +1. Next, on day 18 they are irradiated again followed by the infusion of HLA matched 5X106/mouse = 1.7 X 108/kg MILs or PBLs (Noonan, 2015, Cancer J 21: 501-5). This assay can be used to measure the persistence of the MILs as well as their ability to destroy tumor. In this assay, the MILs persist and infiltrate the bone marrow while the tumor continues to grow in the PBL treated mice. By delaying the infusion of the MILs (thus allowing more growth of the tumor) we can mitigate the efficacy of the MILs. Both in this model and in vivo in patients, it is clear that increased persistence of MILs is associated with increased efficacy (Noonan,2015, Sci Transl Med 7: 288ra78). In Aim 2 and 3 we seek to develop means of enhancing T cell fitness with regard to persistence and memory generation. Thus, we will generate MILs in the metabolically defined media (Aim 2) or in the presence of JHU3202-01 (Aim 3) and test their persistence and efficacy in this model. We predict, that the MILs expanded in the defined media or the presence of JHU3202-01 will persist longer and thus be more effective in eradicating tumor in this model.

Push-Pull relationship:

Aims 2 and 3 of TR&D 3 will be developed using mouse T cells. This CP provides the extraordinary opportunity to test these “tools” using MILs, unique T cells currently being applied in ACT. In as much as persistence of MILs in vivo is a critical component of their efficacy, the media and small molecules developed in Aims 2 and 3 might greatly accelerate the clinical development of this approach (push). In addition, in as much as the Borrello lab has already noted that growing MILs under hypoxic conditions improves their persistence, Aim 2 has the potential to provide important mechanistic insight to this observation (pull). In addition, the data/ resources and reagents from this CP will be of great utility to WindMIL Therapeutics, a Biotechnology company that is clinically developing MILs for the treatment of cancer (push). They in turn can provide for us clinical grade MILs to test, refine and accelerate the technology developed in the CP toward clinical application (pull).