Advancements in genetically engineered cell therapies have demonstrated early efficacy and safety in patients with blood disorders for whom standard treatments have been unsuccessful, according to data showcased this week at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans. The conference, which runs December 7-10, 201,3 is the premier hematology event of the year.
Many patients are being newly diagnosed with blood disorders – ranging from cancer to rare genetic conditions – that respond well to modern treatment regimens. However, for more than half of newly treated patients, therapies fail to work or patients experience a relapse that may negatively affect their prognosis. An emerging field, dubbed “precision medicine,” aims to improve success rates by attacking specific targets that are responsible for a patient’s disease. Using a patient’s own re-engineered cells to attack their disease is an example of this approach. Building on the existing concept of turning the immune system into a disease-fighting weapon, this new field of medicine adds innovative technologies that transform healthy cells into “super” cells that can more effectively combat disease.
Several studies presented during the New Orleans meeting detailed results using one method known as chimeric antigen receptor (CAR) cell engineering. The CAR process starts when T cells (naturally occurring immune cells) are extracted from the blood of an individual and outfitted with two powerful features: a receptor on the outer cell surface that recognizes a protein called CD19 present on most leukemic cells and a powerful mechanism inside the cell that triggers it to expand and proliferate once attached to the targeted protein. With these new engineered features, the T cells are injected back into the patient, now primed to seek and destroy cancer cells.
Studies on the CAR approach provide data on both adult and pediatric patients with leukemia who have responded well to this treatment strategy. Preliminary studies have found that this process may generate responses in as many as two-thirds of cases in which all other treatment options have failed. Further, because the cells are derived from the patient, there is an inherently lower risk of toxicity because the cells are less likely to attack the host tissue than cells introduced from a foreign body.
Other advances in cell engineering reported today include a new generation of gene “vector” therapy that self-destructs once it delivers critical, missing genetic material to a patient, solving the issue of T cell overgrowth observed in previous studies. Finally, genetic modifications of haploidentical (or half-matched) stem cells prior to transplant could expand the utility of this treatment approach to a much wider range of patients in the coming years by reducing the risk of transplant infections.
“It’s exciting to see these encouraging initial results with engineered immune cells, particularly such a durable response among patients who have very aggressive disease that has relapsed after standard treatments,” says Dr. Laurence Cooper, M.D., Ph.D., Professor (Tenured) in the Department of Pediatrics Patient Care, Division of Pediatrics at the University of Texas MD Anderson Cancer Center in Houston. “With the right technology and laboratory expertise, the process of cell engineering is feasible for many patients. One remaining challenge is determining why some patients benefit and others have less durable responses. Does ‘one size fits all’ therapy work or do we need personalized or individualized T cell treatments? Further, we need to extend these studies to other tumor types, particularly solid tumors, to evaluate their potential in other clinical settings.”
Dr. Cooper joined the M.D. Anderson Cancer Center in 2006 and currently leads the Pediatric Cell Therapy service (formally named the BMT program). In addition to caring for children, adolescents and young adults undergoing autologous and allogeneic hematopoietic stem-cell transplantation (HSCT), Dr. Cooper runs a laboratory translating immunology into clinical practice. His program has multiple investigator-initiated trials that infuse T cells and NK cells to target malignancies. The adoptive transfer of lymphocytes represents the future of HSCT as he and other investigators enhance the potency of the immune system to eliminate residual cancers.
The Cooper laboratory at the MD Anderson Center works to translate basic immunologic concepts into therapeutic trials using a research plan built upon the premise that augmenting a host’s immune response through adoptive transfer of NK cells and T cells can eliminate infection and malignant cells. Currently, we are using a strategy to selectively enhance a patient’s immunity by infusing NK cells and T cells that have been rendered specific for pathogens and neoplasms, in compliance with current good manufacturing practice for Phase I/II trials.
In a profile of his lab’s research, Dr. Cooper notes that they have used gene therapy to improve the potency of immunotherapy and to target tumor antigens for which there is immunological tolerance — achieved by combining two technologies to genetically modify clinical-grade T cells, (i) namely electro-transfer of Sleeping Beauty (SB) system and (ii) selective propagation on artificial antigen presenting cells (aAPC). This has resulted in the lab’s launching a suite of gene therapy trials infusing tumor-specific T cells.
Dr. Cooper notes that T-cell specificity can be redirected through the expression of single-chain chimeric antigen receptors (CARs) that recognize cell-surface molecules independent of MHC. For example, a CD19-specific CAR can be expressed to render T cells capable of targeting malignant B cells and his team are undertaking a first-in-human trial to infuse such genetically modified T cells after autologous hematopoietic stem-cell transplantation (HSCT). CAR+ T cells can also be readily generated with specificity for other antigens, such as the ancient retroviral protein HERV-K expressed on breast cancer, CD56 expressed on neuroblastoma, and c-Met expressed on many hypoxic tumors.
Since the therapeutic effect is dependent on T-cell persistence the researchers have adapted the CAR itself, co-expressed co-stimulatory molecules, as well as altered the culturing environment to reprogram T cells for sustained persistence. To infuse donor-derived CAR+ T cells after allogeneic HSCT and avoid graft-versus-host-disease they have expressed CAR in T cells that have been anergized against allo-antigen and used designer zinc finger nucleases (ZFNs) to eliminate expression of endogenous ab T-cell receptor (TCR) on CAR+ T cells. To build upon data showing the persistence and anti-tumor effect of adoptive transfer of human CAR+ T cells in immunocompromised mice we are using two large animal models.
Dr. Cooper says they have demonstrated that the infusion of autologous T cells in companion dogs with spontaneous B-lineage lymphoma can help restore immunity, traffick to lymph nodes and improve survival, using Rhesus monkeys to model the persistence of CAR+ T cells and effects of targeting a B-lineage antigen on normal B cells in non-human primates. To non-invasively image infused T cells we have (i) co-expressed thymidine kinase (TK) as a reporter gene for positron emission tomography (PET) and (ii) electro-transferred, the lab uses its proprietary high throughput device, 64Cu-labeled gold nanoparticles. To improve the safety of CAR+ T cells Dr. Cooper explains that they have adapted the SB system to express multiple transposons to co-express CAR with TK to render T cells sensitive to conditional ablation in vivo with ganciclovir. Furthermore, they have introduced a molecular sensor for oxygen so that the CAR is conditionally expressed on T cells in the hypoxic tumor microenvironment.
To target pathogens in addition to malignancies thry are developing CARs that recognize CMV and Aspergillus. Since the aAPC supports the outgrowth of CAR+ T cells, we have adapted this platform for the numeric expansion of antigen-specific T cells that recognize pathogens and malignancies via TCR. To combine T-cell therapy with vaccine therapy we have genetically modified T cells to express immunodominant antigens from tumors and pathogens and demonstrated that these can serve as T-cell derived antigen presenting cells (T-APC). To broaden the appeal of T-cell therapy, we have generated ZFNs to eliminate MHC expression so that allogeneic CAR+ T cells can be pre-prepared and infused as an “off-the-shelf” reagent across transplantation barriers.
Novel immunotherapy for treatment of B-cell leukemia, lymphoma, and multiple myeloma are being designed for clinical trials at the Cooper lab, using T cells genetically modified to express chimeric antigen receptors (CARs). These CARs redirect the specificity of NK cells and T cells from umbilical cord blood and peripheral blood for desired cell surface tumor antigens. Non-invasive imaging technology using bioluminescence and positron emission tomography are used to describe the persistence and distribution of the infused cells. Gene transfer is accomplished using non-viral and viral vectors. Ex vivo expansion technology uses artificial antigen cells to propagate the genetically modified lymphocytes. Complex expression vectors are used to probe the activation state of the genetically modified cells as well as co-express suicide genes for conditional ablation in vivo should toxicities arise. Mouse animal models are used to assess the therapeutic potential of the genetically modified lymphocytes. These data sets form the basis of gene therapy clinical trials. Follow up studies from the recipients evaluate not only the safety and feasibility of the immunotherapy, but also determine the biodistribution of the infused cells and evaluate how the immunotherapeutic potential can be improved.
Other study presentations at the New Orleans meeting include:
Removal of Alpha/Beta+ T Cells and of CD19+ B Cells From the Graft Translates Into Rapid Engraftment, Absence of Visceral Graft-Versus-Host Disease and Low Transplant-Related Mortality in Children With Acute Leukemia Given HLA-Haploidentical Hematopoietic Stem Cell Transplantation by Alice Bertaina, MD, of the Bambino Gesu Children’s Hospital in Rome, Italy. “Our results, which demonstrate that transplantation of selectively modified, half-matched donor stem cells boasts success rates equivalent to those of a fully matched transplant, preventing GVHD and reducing transplant-related death, help continue to establish this approach as a viable option for patients without a matched donor,” said Dr. Bertaina. “This has the potential to make this lifesaving treatment more accessible to a much larger population of patients who may not have a perfect donor match.”
Immune Reconstitution and Preliminary Safety Analysis of 9 Patients Treated With Somatic Gene Therapy for X-Linked Severe Combined Immunodeficiency (SCID-X1) With a Self-Inactivating Gammaretroviral Vector by Sung-Yun Pai, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston, Mass. “We have preliminary evidence that using this new vector approach is just as effective but may eliminate the long-term risk of leukemia in these children,” comments Dr. Pai “We will need to closely monitor these patients to evaluate their long-term risks, but at this point we are hopeful given the excellent response so far.”
Long-Term Functional Persistence, B Cell Aplasia and Anti-Leukemia Efficacy in Refractory B Cell Malignancies Following T Cell Immunotherapy Using CAR-Redirected T Cells Targeting CD19 by Michael Kalos, PhD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.
“These new and expanded data provide significant proof that T cells engineered to express cancer-targeting chimeric antigen receptors not only work, but work dramatically and in a sustained manner in patients with relapsed, treatment-resistant leukemia, and further demonstrate the potential of this approach to help these patients achieve complete response,” said Dr. Kalos. “Further, our results show that we can potentially measure and track the activity of these engineered cells in the body as a way to monitor treatment, an exciting finding considering that this treatment is often the last hope for these patients.”
T Cells Engineered With a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Produce Significant In Vivo Proliferation, Complete Responses and Long-Term Persistence Without GVHD in Children and Adults With Relapsed, Refractory ALL by Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia, Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. Our results serve as another important milestone in demonstrating the potential of this treatment for patients who truly have no other therapeutic options,” said Dr. Grupp. “These data also demonstrate that these engineered hunter cells greatly expand and then persist in patients, allowing for long-term disease control. This allays previous concerns that infused cells only survive for a limited time. In the relatively short time that we’ve observed these patients, we have reason to believe that this treatment could become a viable therapy for their relapsed, treatment-resistant disease and we look forward to continuing to evaluate their long-term response.”
Effective Treatment of Chemotherapy-Refractory Diffuse Large B Cell Lymphoma With Autologous T Cells Genetically-Engineered to Express an Anti-CD19 Chimeric Antigen Receptor by James Kochenderfer, MD, of the Experimental Transplantation and Immunology Branch of the National Cancer Institute at the National Institutes of Health in Bethesda, Md. “Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable,” notes Dr. Kochenderfer. “We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B cell lymphomas who had exhausted all other treatment options. This approach offers an option for patients with chemotherapy-refractory large B cell lymphomas who are not generally thought to be good candidates for hematopoietic stem cell transplantation. This approach is still an early-stage experimental therapy, and we will continue our research to further improve the protocol and evaluate its value in additional patients with treatment-resistant disease.”
In addition to the research studies cited above, below, two additional data sets are being presented on this research program during the meeting:
4162 Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019 cells) Have Long-Term Persistence and Induce Durable Responses In Relapsed, Refractory CLL – corresponding author: David L. Porter, MD of the Multiple Myeloma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
873 Randomized, Phase II Dose Optimization Study Of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) In Patients With Relapsed, Refractory CLL, also lead-authored by David L. Porter, MD of the Multiple Myeloma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
The American Society of Hematology (ASH) (http://www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (http://www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.
American Society of Hematology
The University of Texas MD Anderson Cancer Center