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
  1. 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.
  2. 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.
  3. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/ les/kymriah.pdf.
  4. Yescarta [prescribing information]. El Segundo, CA: Kite Pharma; 2017. yescarta.com/ wp-content/uploads/yescarta-pi.pdf.
  5. 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.
  6. 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.
  7. Park JH, RivieĢ€re 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.