Making Allogeneic Cell Therapy a Reality for Patients: An Interview With Allogene Therapeutics

Clinical-stage biotechnology company Allogene Therapeutics is focused on one singular goal: making allogeneic chimeric antigen receptor T cell (AlloCAR T^TM) therapies and their potential a reality for patients.

Autologous CAR T therapies have proven to be one of the most significant therapeutic developments in recent history. However, the patient being the source of the T cells poses several limitations. Allogene's AlloCAR T^TM therapy utilizes T cells from healthy donors that are stored for off-the-shelf delivery to patients.

Technology Networks spoke with David Chang, MD, PhD, President, Chief Executive Officer and Co-Founder of Allogene to learn about the recent developments in this fast-developing research space, the applications of AlloCAR T^TM therapy, and Allogene's visions for the future.

Molly Campbell (MC): What were some of the major highlights for Allogene in 2019?

David Chang (DC): 2019 was a highly successful year for Allogene. We accomplished all of our corporate goals, established leading capabilities across multiple new functions, expanded our senior management team, and most importantly, we initiated two clinical programs, ALLO-501 in relapsed/refractory non-Hodgkin lymphoma and ALLO-715 in relapsed/refractory multiple myeloma.

As we look to 2020, all 200-plus employees at Allogene remain singularly focused on one goal: making AlloCAR T^TM therapies and their life-saving potential a reality for patients. The team at Allogene intends to strengthen our leadership position in AlloCAR T^TM therapy and we recently laid out our three-part strategy to achieve this goal:

• Establish an industry-leading platform
  
  
• Validate that platform through the rapid clinical development of multiple product candidates
  
  
• Transform the future of allogeneic CAR T by advancing next-generation technologies

We believe our company remains well positioned to be a leader in the highly innovative, dynamic, and potentially revolutionary field of AlloCAR T^TM therapy.

MC: In Allogene's opinion, what key trends can we expect to see in the development of cell therapies in 2020?

DC: I truly believe that we are on the cusp of new breakthroughs in this field and that the evolution of engineered cell therapy has the potential to expand beyond cancer. Engineering, synthetic biology and gene editing has opened the door beyond allogeneic cell therapy. There is a bright future with transformative technologies that may hold the key to addressing solid tumors.

MC: Could you highlight some of the limitations of autologous CAR T therapies and the benefits of allogeneic CAR T cell therapies?

DC: Autologous CAR T therapies are one of the most significant treatment breakthroughs in recent history but they do have certain limitations that can come with first generation therapies, primarily because the patient is the source of the T cells used to create the therapy. There is a lengthy vein-to-vein time due to the individualized manufacturing process. These patients have a poor prognosis, so time is of the essence, and because of the wait time, not all indicated patients may receive therapy. In addition, because the therapy begins with a patient’s T cells, the treatment can have variable potency. Lastly, each treatment is individualized requiring its own manufacturing run. This leads to inefficiency of scale and the inability to create inventory for on off-the-shelf treatment.

AlloCAR T^TM therapy uses T cells from healthy donors and are stored for off-the-shelf delivery to patients. We believe that at scale one manufacturing run has the potential to create approximately 100 therapies, resulting in significant scale and more consistent cell products. And, because the starting materials are from healthy donors, we believe we can expect enhanced cell potency and more predictable safety and efficacy.  Our goal is to make AlloCAR T^TM cell products readily available to the patients who can potentially benefit from the treatment in a more affordable way by reducing the manufacturing cost.

MC: What key challenges exist in the development of AlloCAR T^TM candidates? How do Allogene hope to overcome such challenges going forward?

DC: While there are similarities between allogeneic and autologous cell therapy, there are key self / non-self-immune differences that need to be overcome. These include the need to reduce the risk of graft-versus-host disease (GvHD) and to prevent early graft rejection. Our novel platform approach to creating an allogeneic therapy is based upon TALEN gene editing and the use of a novel lymphodepletion strategy.

TALEN technology allows us to efficiently edit out the T cell receptor from AlloCAR T^TM cells. Early data from studies on our UCART19 candidate, as well as data being generated by others in the field, support the view that cells lacking this T cell receptor reduce the risk of a graft versus host response. The second challenge, the ability to overcome graft rejection, is what we believe may now be the key to unlocking the power of AlloCAR T^TM therapy and why a traditional lymphodepletion regimen may not be enough.

We believe our lymphodepletion strategy, based upon the use of ALLO-647, our proprietary anti-CD52 antibody, differentiates us from others and is well suited to prevent early rejection of our AlloCAR T^TM therapy. We use ALLO-647 for the purpose of creating a deep, selective and durable period of lymphodepletion. We believe this window of host immune suppression will facilitate growth and persistence of our allogeneic cells, which have been modified to be resistant to the effects of ALLO-647. By reducing risk of premature rejection, we believe our cells will have more of an opportunity to attack and eradicate cancer cells. ALLO-647 provides us with a unique opportunity to explore the optimal window for AlloCAR T^TM cell expansion and persistence in a variety of clinical settings.

MC: Are you able to tell us more about the latest developments in Allogene's pipeline?

DC: Our goal is to always remain at the forefront of innovation in the field of AlloCAR Tä therapy. This will require us to research and develop next generation technologies derived from internal and external sources.

Our internal research team has developed a novel and potentially transformational technology that is designed to activate our AlloCAR T^TM cells by mimicking the effects of cytokine stimulation. We call this technology TurboCAR^TM. By selectively providing a cytokine activation signal to CAR T cells, TurboCAR^TM has the potential to increase their potency and persistence. Pre-clinical research has demonstrated that TurboCARs^TM may increase efficacy in in vivo models and we are excited to move toward the next stages of development. We have named ALLO-605 as our lead anti-BCMA TurboCAR^TM candidate. ALLO-605 is advancing in preclinical development with an IND planned for 2021.

We have entered into a clinical collaboration with SpringWorks Therapeutics to evaluate ALLO-715 in combination with their investigational gamma secretase inhibitor nirogacestat in patients with relapsed or refractory multiple myeloma. Emerging clinical data suggest that gamma secretase inhibition may augment the anti-tumor efficacy of BCMA-targeted autologous CAR T therapy. We expect to initiate a combination trial of nirogacestat and ALLO-715 in the second half of this year.

We are also expanding our clinical pipeline by advancing AlloCAR T^TM candidates targeting promising targets.  Our team have officially nominated ALLO-316, our anti-CD70 program as our next AlloCAR T^TM clinical candidate. We are excited by the opportunity to bridge hematologic malignancies and solid tumors with ALLO-316. Our focus for ALLO-316 will be on acute myeloid leukemia (AML), T-cell malignancies and renal cell carcinoma (RCC).  We expect to submit an IND by the end of this year.

In the longer-term, our collaboration with Notch Therapeutics is off to a strong start. Our research teams are working together to design and create AlloCAR T^TM cells using an induced pluripotent stem cells, or iPSC-based starting material. Success on this front could enable a more streamlined supply chain, greater cell product consistency, and the potential to create more highly engineered therapies.

David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder, was speaking to Molly Campbell, Science Writer, Technology Networks.