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Letter from the Editor

Dear JITC Readers,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

JITC Editor Picks

DASATINIB FOR TREATMENT OF CAR T-CELL THERAPY-RELATED COMPLICATIONS

Summary:

Blockade of IL-6 and steroids are the current standard of care for the treatment of CAR T cell therapy-associated cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Katharina Baur and colleagues describe a case report of complete resolution of steroid- and IL-6 blockade refractory CRS and ICANS after treatment with dasatinib. Murine models and in vitro studies have previously shown that dasatinib induces a reversible inactive state in CAR T cells, but there have not been any published clinical data on the use of this agent in the management of CRS or ICANS. In this case, a man in his late 60s with relapsed diffuse large B cell lymphoma received an infusion of 3.9×10⁸ CAR positive viable T cells after lymphodepleting chemotherapy with fludarabine and bendamustine. Grade 3 CRS developed on day 3 after infusion, and on day 7 he experienced hallucinations, sensory aphasia, apraxia, and disorders of consciousness corresponding to ICANS grade 4. Neither CRS nor ICANS responded to treatment with IL-6 blockade with five doses of tocilizumab and a single dose of siltuximab nor continuous dexamethasone. With consent from family members, dasatinib was administered off-label, starting on day 7. Body temperature normalized within 48 hours and the patient was extubated after 1 day. After 7 days of dasatinib treatment, he was transferred out of the intensive care unit awake and in an adequate neurological state. Neither CRS nor ICANS rebounded. Although the influence of prior immunosuppressants or the natural history of CRS and ICANS cannot be ruled out, this impressive case offers rationale for further investigation of dasatinib in the management of CAR T cell therapy-related toxicities.

EFFICIENT PRECLINICAL TREATMENT OF CORTICAL T CELL ACUTE LYMPHOBLASTIC LEUKEMIA WITH T LYMPHOCYTES SECRETING ANTI-CD1A T CELL ENGAGERS

Anaïs Jiménez-Reinoso, Néstor Tirado, Alba Martinez-Moreno, Víctor M Díaz, Marina García-Peydró, Oana Hangiu, Laura Díez-Alonso, Ángela Albitre, Petronila Penela, Maria L Toribio, Pablo Menéndez, Luis Álvarez-Vallina, Diego Sánchez Martínez

Journal for ImmunoTherapy of Cancer 2022;10:e005333. (23 December 2022)

RESEARCH

Summary:

The potential for fratricide and limited numbers of non-cancer effector T cells has hindered the development of T cell redirecting strategies such as bispecifics and CAR T cell therapies for the treatment of T cell malignancies. Anaïs Jiménez-Reinoso and colleagues demonstrate preclinical efficacy for T cells engineered to secrete a CD1a x CD3 bispecific against cortical T cell acute lymphoblastic leukemia (coT-ALL). CD1a is a surface receptor that is highly expressed on coT-ALL blasts, yet minimally present on healthy tissues. In vitro, T cells engineered to secrete the bispecific eliminated target cells at a lower effector to target ratio than anti-CD1a CAR T cells. Furthermore, the bispecific-secreting T cells mediated bystander-dependent killing of non-engineered T cells in a non-contacting transwell culture system. In patient-derived xenograft models, the bispecific-secreting T cells eliminated leukemia with comparable efficacy as CD1a-directed CAR T cells. These preclinical data illustrate the advantages of T cell engineering approaches beyond CAR T in settings where limited numbers of effector T cells are available for manufacturing.

LONG-TERM OUTCOMES WITH NIVOLUMAB PLUS IPILIMUMAB VERSUS SUNITINIB IN FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED SARCOMATOID RENAL CELL CARCINOMA

Brian I Rini, Sabina Signoretti, Toni K Choueiri, David F McDermott, Robert J Motzer, Saby George, Thomas Powles, Frede Donskov, Scott S Tykodi, Sumanta K Pal, Saurabh Gupta, Chung-Wei Lee, Ruiyun Jiang, Nizar M Tannir

Summary:

Sarcomatoid differentiation is an aggressive subtype of renal cell carcinoma (RCC) that is associated with a poor prognosis. In this exploratory post hoc analysis of the phase III CheckMate 214 trial, Brian I Rini and colleagues report long-term survival benefit for patients with sarcomatoid RCC who were treated with ipilimumab in combination with nivolumab. CheckMate 214 was a global, multicenter, open-label, randomized phase III trial that was the basis for United States Food and Drug Administration approval for combination ipilimumab plus nivolumab for the first-line treatment of advanced intermediate- or poor-risk RCC. Independent central pathology review of archival tumor tissue identified a total of 139 patients with sarcomatoid RCC, 74 of whom were treated with ipilimumab plus nivolumab and 65 of whom were treated with sunitinib. At 5 years minimum follow up, the median OS for the patients in the ipilimumab plus nivolumab arm was 48.6 months compared to 14.2 months in the sunitinib arm (hazard ratio 0.46). The median duration of response was not reached in the ipilimumab plus nivolumab arm and 12% of patients remained on treatment. Among the 45 patients with objective response to ipilimumab plus nivolumab, 22 discontinued therapy and never received subsequent therapy and the median treatment-free interval (TFI) was 26.5 months. For the sunitinib arm, the median TFI for patients with an objective response was 15.9 months. These data demonstrate durable benefit with immunotherapy in a disease setting that formerly had few effective therapeutic options, further reinforcing the status of ipilimumab plus nivolumab as the preferred first-line regimen for sarcomatoid RCC.

SERUM ALBUMIN: A PHARMACOKINETIC MARKER FOR OPTIMIZING TREATMENT OUTCOME OF IMMUNE CHECKPOINT BLOCKADE

Summary:

IgG antibodies and serum albumin both have long half-lives in plasma, in part, because they are salvaged from intracellular degradation and recycled into the extracellular milieu by the neonatal FcRn receptor. Based on this shared mechanism of homeostatic regulation, Ming Zheng presents a hypothesis that baseline serum albumin levels could be used as an inexpensive and easily accessible biomarker to predict efficacy of immune checkpoint inhibition. In a retrospective analysis that included 1,479 patients with a variety of cancers who received PD-(L)1 and CTLA-4 blockade, increasing baseline serum albumin levels were significantly associated with stepwise improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The association between serum albumin and PFS, OS, and ORR was maintained across different demographic and clinical subgroups, with the exception of sarcoma and pancreatic cancer, as well as between a pooled group of highly immunotherapy-responsive tumors (ie, melanoma, renal cell carcinoma, esophageal cancer, endometrial cancer, gastric cancer, non-small cell lung cancer, colorectal cancer, small-cell lung carcinoma, and head and neck cancer) and all low-responsive tumors (ie, sarcoma, bladder cancer, ovarian cancer, breast cancer, mesothelioma, hepatobiliary cancer, and pancreatic cancer). These analyses set the stage for future biomarker and interventional studies to both characterize and optimize the relationship between the pharmacokinetics of immune checkpoint inhibitor antibodies and clinical outcomes.

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