NEW: August 2, 2011 ―
The SWCRF Announces $25,000 Grant in B-cell Lymphoma

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Richard J. O’Reilly, M.D.
Chairman, Department of Pediatrics
Chief, Bone Marrow Transplantation Services

Claire L. Tow
Chair in Pediatric Oncology Research

Dear Friends of the Max Cure Foundation,

I am writing to you all to express the heartfelt thanks of the Department of Pediatrics and
the Immune Cell Therapy Laboratory at Memorial Sloan-Kettering Cancer Center for your
continued support of our research and clinical investigations on immune cell therapies for the
treatment of lymphomas and leukemias in children. I also wish to provide you all with an update on the progress that has been made over the last two years.

Our studies of immune cell therapy began several years ago when we first discovered
that small numbers of immune cells, called T-cells, generated in response to Epstein-Barr Virus
(EBV), the virus that causes infectious mononucleosis, could induce permanent remissions of a
type of lymphoma caused by this virus that develops in 3-10% of patients who have received a
heart, kidney or marrow transplant. Our findings were rapidly confirmed by many transplant
centers all over the world. However, the time and specialized facilities needed to make these
cells and the perception that only fully tissue-typed or HLA matched T-cells grown from the
blood of the patient or a marrow transplant donor could be used, thwarted the broad and rapid
application of this curative treatment. This perception was based on the fact that immune T-cells identify and kill virus-infected lymphoma cells only if they express, on their surface, fragments of the virus’s proteins packaged together with an identity card, called a human leukocyte antigen (HLA), shared by the immune T-cell.

Over the last 2 years, with the support of the Max Cure Foundation, we have developed
a bank containing EBV-immune T-cells grown from the blood of over 200 consenting normal
marrow transplant donors. We’ve also shown that T-cells selected from this bank that are only
partially HLA-matched but can recognize EBV together with one shared HLA molecule can be
used to treat and cure EBV-associated lymphomas in patients for whom a fully-matched
immune donor is not available. Of the first 13 patients we’ve treated, 9 have experienced either a complete remission or partial tumor regressions that have been sustained for at least 1-2 years. As a result of this advance, we can now provide immediate access to immune T-cells for over 90% of patients who develop this form of lymphoma. Our initial success in patients who developed EBV positive lymphomas following an umbilical cord blood transplant will be published in the journal Blood. Our extended experience was recently presented at the
International Transplantation Congress in Vancouver.

We have also developed two new systems for making immune T-cells that can seek out
and selectively kill lymphoma and leukemic cells both in the test tube and in the body. One of
these approaches is particularly applicable to the vast majority of non-Hodgkin’s lymphomas
and to most common forms of acute lymp_hoblastic leukemia in children. In this treatment
approach, T-lymphocytes are isolated and expanded from samples of the patient’s blood and
then infected with a friendly virus designed and developed by Drs. Michel Sadelain and Renier
Brentjens at MSKCC. This virus inserts genetic information into the T-cells that does not hurt the cell but directs it to express an antibody-like receptor on its surface that will bind to malignantlymphoma and leukemic cells. When these retargeted T-cells encounter and bind to malignant cells in the body, the T-cells are then activated and kill the malignant cells. In animal models, these T-cells can eradicate established lymphoma transplants in immune deficient mice. Results of these studies have been published. Currently, our center is conducting an FDA approved phase I trial of these genetically engineered T-cells in the treatment of patients with chemotherapy-resistant disease. However, it is too early to assess their clinical impact.

Recently, in collaboration with Drs. Brentjens and Sadelain we have further modified this
approach so that we can now safely use retargeted T-cells grown from the blood of a normal
donor to treat relapses of ALL or NHL or prevent their occurrence after a marrow transplant. For this treatment, we initially generate EBV-immune T-cells using blood samples from the
transplant donor. Because of the way these immune T-cells are produced, they are only
reactive against EBV and have no ability to react against the patient’s normal tissues (a
potentially lethal reaction called graft vs host disease). We then genetically engineer these Tcells to also express the antibody-like receptor that reacts against ALL or NHL cells, and use
these cells for immune therapy. These T-cells can now eliminate both ALL or NHL cells as well
as EBV-infected cells. Because of the long life of EBV-immune T-cells, they should also provide
much longer protection against ALL or NHL. A trial of these T-cells is being submitted for FDA
review.

The second approach developed with support by the Max Cure Foundation for treatment
of patients with leukemia exploits the anti-tumor activity of T-cells grown in the test tube that are immunized against proteins that are expressed uniquely or at markedly higher levels in cancer cells than in normal cells. One such protein is called the Witms tumor protein, or WT-I. WT-1 is important for the embryonic development of the kidneys and reproductive organs, but is expressed at only minimal levels in the tissues after birth. In contrast, WT-1 is highly expressed by malignant cells in acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and several solid tumors, including cancers of the ovary, breast, kidney and colon. Recently, our laboratory has identified a large, heretofore unrecognized series of peptides in the amino acid sequence of the WT-1 protein that can be used to immunize T-cells from cancer patients and normal donors. We’ve also shown that T-cells immunized with each of these peptides can efficiently kill ALL, AML, ovarian carcinoma and colon carcinoma cells expressing the WT-1protein in cell culture and can induce remission when transfused into immune deficient mice bearing transplants of these human tumors. Based on our results, the FDA has granted an investigational drug permit (IND) to initiate clinical trials of these WT-1 immune T-cells. We are currently conducting two trials: one evaluating transfusions of donor-derived WT-1 immune Tcells in patients who have relapsed following a marrow transplant; the other evaluating patient derived WT-1 immune T-cells in women with relapsed ovarian carcinomas.

In summary, we have developed a series of new immune T-cell based therapies for the
treatment of lymphomas and leukemias in children which have exhibited striking anti-tumor
activity both in cell culture assays and in immune deficient mice that support the growth of
human tumor transplants. Our results in these model systems and our systems for
manufacturing these immune T-cells have provided the evidence of safety and activity required by the FDA to initiate clinical trials. These trials are now in progress. We have also radically altered the scope of our original studies of immune T-cells applied to the treatment of EBVassociated lymphomas. While the bank of EBV-immune T-cells which we have established will need further development, we believe we can now provide immediately accessible cellular
therapies for a large proportion of patients affected by these malignancies.

We are encouraged by the results of these initiatives in ceil-based immunotherapies,
and by the fact that we have been able to translate this research into clinical trials. However, the clinical trials are still early in their course and both the demands on resources and the
challenges remaining are immense. The Max Cure Foundation has played a pivotal role in this
effort. Your continued partnership in support of this translational and clinical research is deeply appreciated.

My best to all of you.

Sincerely yours,

Richard J. O’Reilly, MD