Combating Advancing Cancers With CAR T-Cell Therapy

Immunotherapy methods emerged on the oncology market as adoptive cell transfers, specifically chimeric antigen receptor (CAR) T-cell therapies, with clear benefits in hematologic malignancy treatment.

CAR T-cell therapy begins by removing a patient’s lymphocytes, transporting them to a laboratory, and transducing the cells with a DNA plasmid vector that encodes specific tumor antigens. These modified and targeted lymphocytes are then reintroduced to the patient’s body through a single infusion to attack tumor cells. Known as autologous CAR T-cell therapy, this treatment has been in development for more than 25 years, resulting in 4 generations of improving therapy that has generated responses for up to 4 years in some studies.¹

In 2017, CAR T-cell therapy was approved for patients with refractory B-cell aplasias, such as B-cell acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma.² There are 2 approved products on the market, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta), which are available through a Risk Evaluation and Mitigation Strategy program. Kymriah is approved for patients up to 25 years of age with relapsed or refractory (r/r) B-cell precursor ALL and adult patients 18 years and older with r/r large B-cell lymphoma after failing 2 or more lines of systemic therapy.³ Axicabtagene ciloleucel is approved for adults with r/r large B-cell lymphoma following the failure of 2 systemic therapies.⁴

Despite promising results of treatment with either tisagenlecleucel or axicabtagene ciloleucel, patients incur a financial burden of approximately $475,000 and $373,000 for each treatment, respectively.⁵

Patient insurance co-pays vary drastically, depending on insurance coverage. However, patients with Medicare or Medicaid coverage have a maximum out-of-pocket cost of approximately $1340.⁵ These estimates do not include costs associated with receiving treatment, such as hospital stays, supportive care, or physician visits.

The efficacy of CAR T-cell treatment depends on an appropriate immune response. A balance must be achieved between the response and minimizing patient harm. CAR T-cell therapy can cause several toxicities, including cytokine release syndrome (CRS) and CAR T-cell—related encephalopathy syndrome (CRES). CRS often presents as a high fever, flu-like symptoms, or hypotension.¹ CRES generally presents as confusion, irritability, or seizures.⁶ The results of a clinical trial by Park and colleagues at Memorial Sloan Kettering Cancer Center demonstrated that CRS was present in 85% of patients and CRES in 42%. Individuals with a greater disease burden were more likely to experience these complications.⁷ There was 1 complication-related patient death.

Efforts to improve efficacy have included assessing the benefits and potential risks of a second infusion of CAR T-cell therapy. An ongoing study with 20 participants is taking place in China at the Second Affiliated Hospital of Xi’an Jiaotong University.⁸ Another previous study conducted at the University of Pennsylvania had 42 enrollees, but only 3 received a second infusion.⁹ More studies are needed to determine whether retreatment is beneficial and to assess the optimal time between the initial and second infusions.

The development of CAR T-cell therapies for solid malignancies is in the early stages. Solid tumor malignancies, such as breast, prostate, and colorectal cancers, are the most common types of the disease. A majority of cancer-related morbidity and mortality can be attributed to these cancers.¹⁰ Clinical trials are now being conducted to investigate the ef cacy of using CAR T cells to target the inhibitory receptor, PD-1, in progressive solid tumor malignancies.¹¹

The innovation of CAR T-cell therapy has truly shifted the paradigm of treatments for hematologic cancers and has a promising future in solid tumor cancers. It is becoming an emerging candidate for r/r cancers as the technology has improved and continues to be validated. Further research regarding optimal genetic modifications of T cells that target tumor cells, as well as the areas previously mentioned, could greatly improve the safety and utility of CAR T-cell treatment.

Esther P. Black, PhD; Rebecca R. Boehman; Caitlyn V. Bradford; Kaitlin L. Musick; Miley G. Nikirk; Heather N. Wolf

References

• Shank BR, Do B, Sevin A, Chen SE, Neelapu SS, Horowitz SB. Chimeric antigen receptor T cells in hematologic malignancies. Pharmacotherapy. 2017;37(3):334-345. doi: 10.1002/phar.1900.
• Knochelmann HM, Smith AS, Dwyer CJ, Wyatt MM, Mehrotra S, Paulos CM. CAR T cells in solid tumors: blueprints for building effective therapies. Front Immunol. 2018;9:1740. doi: 10.3389/ mmu.2018.01740.
• Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/ les/kymriah.pdf.
• Yescarta [prescribing information]. El Segundo, CA: Kite Pharma; 2017. yescarta.com/ wp-content/uploads/yescarta-pi.pdf.
• Cavallo, J. (2018). Weighing the cost and value of CAR T-cell therapy - The ASCO Post. Ascopost.com. www.ascopost.com/issues/may-25-2018/weighing-the-cost-and-value-of-car-t- cell-therapy/. Accessed March 20, 2019.
• Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study [erratum in Blood. 2018;131(5):587-588. doi: 10.1182/blood-2017-11-817775]. Blood. 2017;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.
• Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018 01;378(5):449-459. doi: 10.1056/ NEJMoa1709919.
• CAR-T Re-treatment for Refractory/Relapsed Multiple Myeloma. clinicaltrials.gov/ct2/ show/NCT03672253?cond=CAR+T&draw=11. Updated December 14, 2018. Accessed March 20, 2019.
• Dose Optimization Trial of CD19 Redirected Autologous T Cells. clinicaltrials.gov/ct2/ show/NCT01747486?cond=CAR+T&draw=30. Updated February 26, 2-19. Accessed March 20, 2019.
• Beatty GL, Haas AR, Maus MV, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol Res. 2014;2(2):112-120. doi: 10.1158/2326-6066.CIR-13-0170.
• Liu X, Ranganathan R, Jiang S, et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016;76(6):1578-1590. doi: 10.1158/0008-5472.CAN-15-2524.