Phase I/Phase II Trial of Allogeneic Hybrid TREG/Th2 Cell (RAPA-501-ALLO) Therapy for COVID-19-Related ARDS

The first-in-human Phase 1 study component will evaluate two dose levels of RAPA-501-ALLO off the shelf cells in patients with COVID-19-related ARDS, with key endpoints of safety, biologic and potential disease-modifying effects. The randomized, double-blind, placebo-controlled Phase 2b study component will evaluate infusion of RAPA-501 ALLO off the shelf cells or a control infusion, with the primary endpoint assessing whether RAPA-501 cells reduce 30-day mortality.

The COVID-19 pandemic is a disaster playing out with progressive morbidity and mortality. As of April 6th, 2021, an estimated 132.1 million people have contracted the virus and 2,866,000 deaths have resulted globally. The United States has the highest totals with an estimated 30.8 million people diagnosed and 556,000 deaths. The United States has the highest totals with an estimated 22.4 million people diagnosed and 375,000 deaths. In stages 1 and 2 of COVID-19, viral propagation within the patient is predominant. As such, therapeutic interventions focus on immune molecules (convalescent serum, monoclonal antibodies) and anti-viral medications (remdesivir). In marked contrast, the most severe and deadly form of COVID-19, stage 3, is driven not by viral propagation, but by an out-of-control immune response (hyperinflammation) caused by increases in immune molecules known as cytokines and chemokines. As such, therapeutic interventions for stage 3 disease focus on anti-inflammatory medications such as anti-cytokine therapy (anti-IL-6 drugs) or corticosteroid therapy. Unfortunately, such interventions do not address the full pathogenesis of stage 3 COVID-19, which includes hyperinflammation due to "cytokine storm" and "chemokine storm," tissue damage, hypercoagulation, and multi-organ failure (including lung, heart, kidney and brain). The pulmonary component of stage 3 disease includes acute respiratory distress syndrome (ARDS), which is a final-common-pathway of patient death due to a myriad of conditions, including pneumonia, sepsis, and trauma. There is a dire need for novel cellular treatments that can deliver both a broad-based immune modulation effect and a tissue regenerative effect, such as RAPA-501-ALLO off-the-shelf allogeneic hybrid TREG/Th2 Cells.

The mechanism of fatal pneumonia in experimental murine coronavirus infection is mediated by innate inflammasome activation, a resultant robust infiltration of inflammatory monocytes and macrophages, and a subsequent increase in multiple pro-inflammatory cytokines and chemokines. Importantly, the CD4+ and CD8+ adaptive T cell response to experimental coronavirus infection can be either curative or disease propagating. Viral-induced pulmonary inflammation has also been evaluated in non-human primate models, which have confirmed that dysregulated immune activation during viral pneumonia involves T cell subset imbalance, a downstream monocyte-derived inflammatory cascade, and resultant epithelial cell injury. In humans, severity of viral-induced lower respiratory tract infection correlates with increased numbers of effector memory CD8+ T cells in the airway. As recently reviewed, human coronavirus infection represents an ongoing battle between virus and host, with the nature of the response dictating disease cure or alternatively, aggravated lung disease. Evidence exists that the adaptive immune system contributes to pulmonary inflammation during SARS-associated Coronavirus (SARS-CoV) disease: that is, bronchoalveolar fluid from such subjects had increased T cell numbers and increased Th1-associated molecules IL-12, IFN-gamma, and IP-10. This downstream adaptive T cell-mediated inflammatory response is driven in part by the SARS-Co-V protein viroporin 3a. Specifically, viroporin molecules activate the NLRP3 inflammasome that links innate-to-adaptive inflammatory responses. Furthermore, both SARS-CoV and SARS-CoV-2 express an open-reading-frame ORF3a molecule, which also activate the NLRP3 inflammasome.

The nature of immunity during resolution of symptomatic COVID-19 infection has recently been reported, namely: emergence of antibody-secreting cells and CD4+ T follicular helper cells; increase in perforin- and granzyme-expressing CD8+ T cells; and relative lack of an increase in pro-inflammatory cytokines and chemokines. In marked contrast, patients with severe COVID-19 disease had greatly increased plasma levels of cytokines (including IL-2 and TNF-alpha) and chemokines (including IP-10 and MIP-1-alpha) (Huang et al., Lancet, 2020). Collectively, these results indicate that pro-inflammatory cytokine and chemokine responses that occur in severe COVID-19 is detrimental and that effective anti-inflammatory approaches may ultimately prove to be therapeutic. However, as previously detailed, the more advanced Stage 3 COVID-19 disease is characterized by an ARDS component, and cytokine storm, as such, novel approaches to treat the COVID-19 viral pneumonia should optimally incorporate both an anti-inflammatory element and a tissue protection/tissue repair element.

Stage 3 COVID-19 carries an estimated 30-day mortality of over 50% in spite of ICU utilization, mechanical ventilation, and supportive care therapies to manage ARDS and multiorgan failure. Narrowly acting targeted anti-inflammatory approaches such as anti-IL-6 therapeutics have not been particularly effective in stage 3 COVID-19 and the broad anti-inflammatory pharmaceutical approach of corticosteroid therapy, has only modestly tempered stage 3 disease in some studies. Cell therapy is also being evaluated in stage 3 COVID-19, in particular, mesenchymal stromal cells (MSC) and now, with the current RAPA-501-ALLO protocol, regulatory T (TREG) cells. TREG therapy has a mechanism of action that includes a multi-faceted anti-inflammatory effect, which puts TREG therapy at the forefront of future curative therapy of a wide range of autoimmune and neurodegenerative diseases, plus transplant complications, such as graft-versus-host disease (GVHD) and graft rejection. In addition, TREG therapy can provide a tissue regenerative effect, which places TREG cell therapy at the lead of novel regenerative medicine efforts to repair a myriad of tissue-based diseases, such as diseases of the skin, muscle, lung, liver, intestine, heart (myocardial infarction) and brain (stroke). RAPA-501-ALLO off-the-shelf cell therapy offers this potential dual threat mechanism of action that incorporates both anti-inflammatory and tissue repair effects for effective treatment of COVID-19 and multiple lethal conditions.