Autologous

• CAR-Ts have a poor safety profile due to cytokine release syndrome (CRS) and neurologic toxicity, which limits their applicability to life-threatening conditions and restricts use to treatment centers with ICU availability and trained staff for post-treatment care
• Considerable investment is required by manufacturers to build and staff facilities to process patient T-cells and guarantee supply chain fidelity, meaning that a clear business case is necessary for new entrants
• Furthermore, given the personalized nature of autologous cell processing, manufacturing economies of scale are hard to come by
• When first launched, centers providing CAR-T therapy made a financial loss on each inpatient Medicare patient they treated, due to high product acquisition costs and uncertain reimbursement levels. There was little incentive for non-academic hospitals to take on this financial burden and risk (see our Mar 2019 in-depth analysis on CAR-T Reimbursement in the US). Reimbursement progress, such as the recent creation of an MS-DRG for CAR-T therapy and changes to the NTAP pathway (described in our Aug 2019 update Our Take on CMS’s Latest Memo on CAR-T Reimbursement) are easing these concerns, but can remain a challenge
• Payers are sensitive to large upfront treatment costs meaning that new pricing and reimbursement models have been needed. Risk-sharing and capped annuity approaches have been considered, but come with implementation challenges in many markets (see our paper on The Payers’ Perspective on Gene Therapies)
• Patients who live far from certified CAR-T centers are burdened by the need to travel long distances with their caregiver(s) for therapy
• High barriers exist for new entrants because treatment centers are incentivized to stick with a single CAR-T ecosystem due to logistical challenges and certification requirements

Allogeneic

• Despite their promise, allogeneic CAR-Ts are in early development and have yet to show compelling/competitive efficacy
• GvHD is a potential issue when using donor cells – mitigation strategies are being developed to reduce this, but need to balance the need to retain high levels of immune activity of the effector cells
• Due to shorter cell persistence, allogeneic CAR-Ts will likely involve a less convenient dosing schedule than autologous CAR-Ts, with patients requiring multiple doses, much like a cycle of chemotherapy or a targeted mAb. The patient/caregiver convenience could be further eroded if allogeneic products cannot expand into wider regional hospitals / the outpatient setting, meaning that patients could need to travel regularly to tertiary care centers
• While allogeneic CAR-Ts have theoretical manufacturing and distribution advantages over autologous, these have yet to be proven at commercial scale; some challenges remain e.g. feasibility of batch culture

Expanding beyond heme-onc

• Scientific barriers to expanding CAR-T therapies to solid tumors remain (e.g. tumor antigen heterogeneity, trafficking and infiltration into tumor tissue, and the immunosuppressive tumor microenvironment¹), greatly limiting CAR-T commercial potential; these barriers need to be overcome and solutions tested in clinical trials
• Expanding CAR-T use into other disease areas, such as autoimmune diseases, will require approaches that greatly improve the side-effect profile to treat non-life-threatening conditions
• Building manufacturing and supply chain capacity for the significantly higher number of patients in ‘non-rare’ diseases will require considerable investment
• As CAR-T therapies move from rare indications to larger indications and therapeutic areas with more diverse competition, they will likely face increased scrutiny from payers who may be strained by increased budget impact. 2019 analysis found that the high reimbursement for cell and gene therapies means that the total costs could exceed what the healthcare system can manage³

Impact of COVID-19

• CAR-T treatment strategies have encountered complications and challenges amid the COVID-19 pandemic, such as staff and resource shortages (e.g. reduced availability of hospital beds and ICU beds), as well as potential delays in shipment of cellular therapy products
• Guidelines have been developed that impact most aspects of care; examples include COVID-19 testing patients within 48-72 hours of lymphodepleting chemotherapy and within 7 days of CAR-T cell infusion, limiting in-person visits and substituting with telemedicine visits, and delaying T-cell apheresis, lymphodepleting chemotherapy, and/or CAR T cell infusion if a patient tests positive²