Breaking Into Cell Therapy: Considerations for Immunology Manufacturers

Cell therapy — a rapidly advancing class of medicines that modify and administer a patient’s immune system cells to fight diseases — has already proven highly effective in treating cancer. Given that success, academic researchers and industry players are increasingly looking more broadly at cell therapy’s potential applications in other therapeutic areas, particularly in immunological and autoimmune diseases. At the start of 2023, there were 538 completed or ongoing clinical studies for the treatment of immunological diseases with CAR-T (chimeric antigen receptor T cell) therapy. Of those, 301 were funded by industry.

Significant therapeutic benefits can potentially be unlocked by harnessing targeted cell therapy in immunological diseases with high unmet needs. CAR-T therapy has emerged as a game-changing treatment in oncology, with six different CAR-T therapies approved for hematological cancers, including leukemia and multiple myeloma, since 2017.¹  CAR-T therapy has proven highly effective in inducing lasting remission in hematological malignancies.²

Beyond CAR-T, other therapies such as CAAR-T (chimeric autoantibody receptor T cell) and CAR-Treg (chimeric antigen receptor T regulatory cell), which have yet to be proven in oncology, appear to have high potential in immunological diseases. As a more specific cell therapy option for fighting autoimmune diseases, CAAR-T therapy works by re-engineering T cells to specifically target autoreactive cells that produce autoantibodies (antibodies that react with self-antigens). CAR-Treg, another cell therapy treatment in the early pre-clinical stage, is receiving greater attention in immunology for its ability to suppress autoimmune responses and maintain homeostasis.

Trends in Cell Therapy Development in Immunology

CAR-T has shown promise in autoimmune diseases due to its ability to destroy autoantibody-producing cells, which are the drivers of many autoimmune diseases. Recent studies have demonstrated positive results of CAR-T treatment in prominent immunological diseases such as systemic lupus erythematosus (SLE).³

Cartesian Therapeutics, Inc., has been conducting a CAR-T therapy trial for myasthenia gravis (MG), a rare autoimmune disease. Because specific autoantibodies involved in MG pathogenesis have been identified, targeting autoantibody-producing cells with CAR-T therapy may halt MG symptoms. Interim results from Cartesian’s Phase 1/2 trial showed sustained efficacy over 10 weeks. These results indicate a positive outlook of expanding CAR-T technology in immunology.

CAAR-T can also be a promising application for diseases with a clearly characterized autoantibody-mediated mechanism driving pathogenesis. One example is Cabaletta Bio’s DSG3-CAART, currently in Phase 1 trial for treatment of pemphigus vulgaris (PV), which causes life-threatening skin blisters. While the monoclonal antibody medication rituximab is an initially effective treatment for PV, 80% of patients experience relapse. Compared to rituximab, CAAR-T may offer durability and potency advantages due to its ability to expand and continue to destroy DSG3 autoantibody-producing cells without repeated dosing and specificity to cells producing autoantibodies against DSG3.

CAR-Treg’s suppressive mechanism of action may have promising applications for autoimmune indications where it can mitigate inflammatory and pathophysiological consequences associated with heightened immune response from these conditions. One prominent area of interest for Treg application is Type I diabetes (T1D) because there is a clear disease pathogenesis and cellular targets to restore function to pancreatic beta cells. Most recent deals and pipeline products related to Treg technology have been for T1D, including Abata Therapeutics’ $95 million Series A funding launch and partnerships between large-cap pharmaceutical companies and biotherapeutic startups.

Other prevalent autoimmune indications such as multiple sclerosis, celiac disease, and irritable bowel disease are attracting Treg funding and preclinical studies because they share a relatively clear disease pathogenesis. Despite existing drugs available for some of these diseases, innovative Tregs provide opportunity to address residual unmet needs in patients that may be underserved by traditional therapeutic options.

Three Key Considerations for Cell Therapy Manufacturers

The ability to successfully deliver cell therapies to patients suffering from autoimmune disease will require: 1) disrupting the right cell mediators of autoantibody production; 2) delivering clinically meaningful benefits that will support a sufficient value proposition for market access; and 3) ensuring patients can access these therapies.

1. The importance of pathophysiology in clinical development

As manufacturers look to address the current unmet needs in the immunology space with cell therapies, specific characteristics of inflammatory and autoimmune diseases will be highly influential to achieving clinical development success. The highly heterogeneous nature and complex signaling pathways driving many chronic autoimmune diseases is a key difference from oncology. Some autoimmune diseases, such as SLE and ulcerative colitis, have multiple immune cell types and autoantibodies involved in driving clinical manifestations of disease. Other diseases have well-defined autoantibodies as a driver of disease pathogenesis, such as DSG3+ in pemphigus vulgaris. Different CAR technologies (e.g., CAR-T, CAAR-T, CAR-Treg) can be employed to target autoimmune diseases, depending on the specific drivers of pathogenesis.

Recent development of CAAR-T and CAR-Treg therapies in autoimmune diseases have shown promise that CAR technologies, beyond traditional CAR-T therapies with broad B cell targets (e.g., CD19, CD20), can be successful in these diseases. As there will likely be rapid development and heightened interest in this area as these technologies demonstrate early clinical trial success, manufacturers can utilize the latest research on disease pathogenesis to drive decisions on where to focus their drug development. For example, a traditional CAR-T with a broad B cell target may be used to treat multiple autoimmune diseases, while a CAAR-T therapy targeting specific autoantibody-producing cells may only be effective for one disease. These clinical factors should be at the core of manufacturers’ CAR therapy portfolio strategies as they determine which immunological indications to prioritize and how to sequence them.

2. Strategies to ensure patient access

CAR-Ts to date have a high price relative to conventional therapeutics in immunology such as molecules and biologics. The pricing potential of CAR-Ts in immunology and the subsequent market access strategy to enable patient access will depend on several factors, including (but not limited to) the strength of the clinical profile, the size of the target patient population, and the need for repeated dosing. Given the number of variables at play and the complexities associated with launching this new therapy class in a new therapeutic area, early market access input into clinical development and overarching strategy becomes even more crucial.

Consideration of market access perspectives early on in clinical development will ensure the highest likelihood of appropriate patient access. Key aspects influencing patient access include patient populations with proven biomarkers expected to drive efficacy outcomes based on mechanism of action, (e.g., PV patients with autoantibodies against DSG3) as well as patient previous treatment status, (e.g., refractory to immunosuppressants). Clear communication of patients who are expected to benefit the most from CAR-T therapy based on science and data will allow payers to develop appropriate coverage and reimbursement criteria to provide therapy to patients in need.

Especially because CAR-Ts in immunology continue to be a one-time therapy, innovative access schemes are expected to play an important role, likely to a greater degree than they have to-date, given evolving payer willingness and ability to implement such agreements. In addition, the “disease-modifying” nature of CAR-Ts in immunology (vs. “life-saving” in oncology) implies that the evidence generation burden will be significant to support the full set of efficacy and safety claims. Innovative access schemes such as outcomes-based agreements combined with annuity payments provide a solution to fairly share risk across manufacturers and payers for these therapies where there may be uncertainties around long-term clinical data at launch.

Providing optimal patient access to CAR-Ts in immunology will undoubtedly require a differentiated approach, compared to what has conventionally been done in this therapeutic area. To get these potentially paradigm-shifting therapies to patients quickly, transparent communication and willingness to partner across manufacturers and payers will be necessary.

3. Advocacy, customer engagement, and support

Manufacturer-provided patient support programs (PSP) have been a central element of CAR-T therapies in oncology due to the high costs and burdens associated with receiving treatment. Current manufacturers of approved oncology CAR-T therapies offer care coordinators and educational resources to support patients in finding a suitable treatment center in their area and becoming comfortable with what to expect from therapy. Some also provide financial assistance with expenses or coordinate logistics related to traveling and lodging at the treatment site.

Manufacturers entering the cell therapy space in immunological indications should have a strong understanding of what support services are required to assist patients logistically, financially, and emotionally as they undergo treatment. To date, advanced therapies in these indications have not required the same sophisticated efforts to support the ecosystem of patient access to treatment. They must therefore consider how existing PSPs for other biologic and small molecule brands may need to be adapted, given the higher level of support required for cell therapy.

It’s also crucial to have an early strategy for customer engagement. For gastroenterologists, dermatologists, rheumatologists, and other immunology specialists, cell therapy is new terrain. Targeted field education and resources are recommended to increase familiarity and comfort with treatment administration, safety, and monitoring protocols. On the practice administration side, staff members will need support when initially learning how to navigate complex processes surrounding the unique billing and reimbursement for these products.

A Moment of Opportunity

Manufacturers should not let these unique clinical development, market access, and customer engagement considerations deter them from pursuing cell therapy technologies for chronic autoimmune and inflammatory conditions. Adopting a deliberate, strategic approach to confronting the nuances of this space increases their chances of reaping all the benefits cell therapy has to offer in immunology. Organizations that pave the way will play a critical role in shaping the future of medicine in immunology while helping countless patients access life-altering treatments.

Co-Authored by: Youbean Oak, Natalya Stone, Susan Park, Cristina Lee 

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¹Sengsayadeth, Salyka, et al. “Overview of Approved CAR‐T Therapies, Ongoing Clinical Trials, and Its Impact on Clinical Practice.”  EJHaem, 24 Nov. 2021, https://doi.org/10.1002/jha2.338.
² Melenhorst, J. Joseph, et al. “Decade-Long Leukaemia Remissions with Persistence of CD4+ CAR T Cells.” Nature, vol. 602, no. 7897, 2 Feb. 2022, pp. 503–509, https://doi.org/10.1038/s41586-021-04390-6.
³“Price-Transparency-Guide/Schemas/In-Network-Rates at Master · CMSgov/Price-Transparency-Guide.” GitHub, github.com/CMSgov/price-transparency-guide/tree/master/schemas/in-network-rates. Accessed 30 June 2023.