Advances in Hematologic Malignancies
Issue 14, Spring 2021
— Utkarsh Acharya, DO, FACP
The utility of adoptive cell transfer, namely chimeric antigen receptor (CAR) T-cell therapy, has revolutionized the therapeutic landscape of historically, unsalvageable, CD19 expressing B-cell malignancies. The efficacy of anti-CD19 CAR T-cell therapy has rapidly supplanted the use of palliative chemotherapy for many patients with intractable aggressive B-cell lymphomas. To date, CAR T-cell therapy is FDA-approved in the management of relapsed/refractory pediatric and young adult B-cell acute lymphoblastic leukemia,
relapsed/refractory aggressive large B-cell lymphoma, relapsed/refractory follicular lymphoma, and relapsed/refractory mantle cell lymphoma, and — most recently
— in the management of relapsed/refractory multiple myeloma.
Given the capacity for CAR T-cells to induce high response rates and exert durable efficacy in the various settings noted above, expanding the utility of cellular immunotherapy in other hematologic malignancies and solid tumors is a natural progression
of this clinical research. To champion this initiative, Dana-Farber Cancer Institute's Immune Effector Cell (IEC) Therapy program houses not only FDA approved CAR T products but more than 29 adoptive cellular
immunotherapy trials across a wide array of malignancies.
Among these, 14 early phase trials focus on examining the safety and efficacy of IEC therapies through CAR T cells, T-cell receptor (TCR) based therapy, natural killer (NK) cells, and tumor infiltrating lymphocytes (TILs) in a wide spectrum of solid tumors including gastrointestinal
tumors, genitourinary tumors, breast cancer, head and neck cancer, sarcoma, non-small cell lung cancer, and cervical cancer. The administration patterns and immunobiological principles of the numerous cellular therapy approaches vary and are beyond
the scope of this writing. However, it suffices to state that each adoptive cellular transfer approach carries its own advantages and drawbacks with respect to immunogenic toxicity and therapeutic target engagement.
The progress to induce categorical efficacy through cellular immunotherapy in the realm of non-liquid tumors is lagging and encumbered due to several factors including the presence of a hostile tumor microenvironment limiting cellular trafficking, paucity
of tumor-specific targets, and potential for immune resistance/escape. Nevertheless, available data from phase I/II studies in various solid tumors intimates much promise.
- For instance, TCRs targeting MAGE-A4, expressed in relapsed/refractory synovial sarcoma, has the capacity to induce response rates of 44% (Pollack S, et al., Cancer Medicine. 2020; 9:4593–4602).
- Additional highlights of interest include the potential of TILs to induce response rates of 36% with durable characteristics among those with relapsed/refractory melanoma (Sarnaik et al., SITC 2019).
- The potential of TILs to exert benefit may further extend to refractory cervical cancer, head and neck cancer, and non-small cell lung cancer, albeit with paucity of robust data to date (Jazaeri et al., ASCO 2019; Creelanet et al., AACR 2020).
Despite the field's nascency, preliminary data described above demonstrates the potential of cell-based therapies to paradigm-shift the management of such solid tumors.
Agnostic of the tumor type, the incorporation of cellular immunotherapy in the management of any cancer is highly nuanced and requires considerations of patient selection, cell source, cell harvesting methodology, manufacturing process, and clinical management
given potential for “on-target” toxicities. Nevertheless, given the rapidly progressive pace of evolving research in the field, it is likely that we will witness additional approvals of novel cellular immunotherapy approaches for solid tumors in the
very near future.
Review current cellular therapy trials at Dana-Farber/Brigham and Women's Cancer Center.