Identification of effective lymphodepletion strategies, optimization of patient selection, and management of novel toxicities remain challenges in the growing field of cellular immunotherapy.
The use of chimeric antigen receptor (CAR)-modified T cells is a promising antineoplastic immunotherapy. As discussed by Drs. Frey and Porter in this issue of ONCOLOGY, it involves genetic manipulation of autologous cytotoxic T cells to create a product capable of targeting specific tumor antigens. In theory, CAR-modified T cells can be developed to target any tumor antigen; however, specificity for tumor rather than host antigens is of paramount importance with regard to limiting toxicity. Because current CAR T-cell treatment approaches employ autologous T cells, issues such as the potential for graft-vs-host disease or the lack of donor availability are of no concern. Due to the early successes of CAR T-cell therapy reported for young patients with relapsed acute lymphoblastic leukemia (ALL) who have exhausted all conventional therapies, it is hoped that treatment with CAR-modified T cells could result in sustained remissions for patients without other therapeutic options.
ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) are B-cell malignancies that, despite recent advances in treatment, still result in a dismal prognosis for patients who become resistant to conventional chemotherapy and immunotherapy. In the early clinical trials of CD19-specific CAR-modified T-cell therapy, the durability of remissions observed in patients with relapsed/refractory hematologic malignancies has been unparalleled by outcomes from clinical trials of other therapies. As Drs. Frey and Porter discuss, the clinical trials with second-generation anti-CD19 CAR T cells have shown remission rates of 70% to 90% to date. Most notably, in a study by Maude et al, 15 of 27 responding pediatric patients with relapsed and refractory B-cell ALL who did not undergo post-remission stem cell transplants have remained in complete remission after 2 years. In studies of CAR T-cell therapy in CLL, while reported overall response rates were not as robust as those seen in ALL trials, long-term molecular remissions were observed. Early data with anti-CD19 CAR T cells in NHL also suggest promising rates of response to treatment.[3,4] Interestingly, the specific lymphodepleting chemotherapy used may determine the duration of remission and overall response rates, especially in ALL and NHL. Although responses to CAR T-cell therapy have been observed without lymphodepletion, this pretreatment process allows superior engraftment and persistence of the CAR T cells in vivo. The optimal lymphodepleting chemotherapy may differ based on the particular malignancy and patient population being treated, and is an area of active investigation.
Ultimately, to extend the promise of CAR T-cell immunotherapy to a substantial number of cancer patients, CAR T cells must be developed that have specificity against the key tumor antigens for a specific tumor type. For example, multiple myeloma has demonstrated sensitivity to cellular immunotherapy with anti-CD19 CAR T cells, even though myeloma cells rarely express CD19. Due to this encouraging activity, three other more commonly expressed antigens-BCMA, CD38, and SLAMF7-are being investigated as potential targets.[5-8]
While the promise of CAR T-cell therapy is alluring, it is also a field in which unique toxicities pose new challenges. Cytokine release syndrome (CRS) and neurotoxicity are two of the more prominent side effects occurring in patients treated with CAR T-cell therapy. CRS has a wide spectrum of presentations, but when severe it can be life-threatening and requires immediate attention. The pathogenesis is thought to involve interleukin-6 secretion triggered by the in vivo activation and proliferation of CAR T cells. For this reason, the monoclonal anti–interleukin-6 antibody tocilizumab is a standard treatment for CRS. The pathogenesis of neurotoxicity caused by CAR T-cell therapy is not as well understood as that of CRS, but it may be associated with bulk of disease or dose and schedule of CAR T cells.
Additional logistical obstacles currently limit widespread application of CAR T-cell immunotherapy. It takes weeks to prepare CAR T cells; the process requires apheresis of autologous T cells, genetic modification and expansion of these cells, and several other steps before they can finally be reintroduced into the patient. This lengthy manufacturing process can be problematic because many patients may suffer from fulminant relapses that do not allow safe delays for cell manipulation and expansion of CAR T cells. In ALL, an additional limitation to optimizing CAR T-cell treatment is that most of the patients studied in clinical trials to date were children or young adults at the time of enrollment; therefore, the ability of older patients with comorbidities to tolerate unique immunotherapy toxicities from CAR T-cell therapy, such as neurotoxicity and CRS, is not well known.
Given that cellular immunotherapy is still in its infancy, there are still more questions than answers with regard to optimal patient selection, CAR T-cell design, and toxicity management. There is active interest in how to best temper the untoward effects of cellular immunotherapy. One attractive avenue could be through insertion of apoptosis-inducing genes that are activated in the presence of drugs. The gene would act as a “safety switch” to allow preferential removal of CAR T cells in case of severe toxicity. Another approach might be to engineer another targetable cell-surface antigen, such as CD20 or epidermal growth factor receptor, to the CAR itself. This would make the CAR T cell susceptible to the agents rituximab and cetuximab, respectively, similarly making possible a selective apoptosis. Such control over the CAR T cells may allow modulation of toxicity and make cellular immunotherapy more broadly applicable to patients who are not likely to tolerate severe CRS.
Identification of effective lymphodepletion strategies, optimization of patient selection, and management of novel toxicities remain challenges in the growing field of cellular immunotherapy. However, as the design of CAR T-cell therapies to treat specific hematologic and solid malignancies continues to evolve, these new approaches hold great promise for many patients with previously incurable malignancies.
Financial Disclosure: The authors have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.
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