Successful chimeric Ag receptor modified T cell therapy for isolated testicular relapse after hematopoietic cell transplantation in an acute lymphoblastic leukemia patient

Yu, Jian; Hu, Yongxian; Pu, Chengfei; Liang, Zhou; Cui, Qu; Zhang, H; Luo, Yi; Shi, Jimin; Jin, Aiyun; Xiao, Lanbo; Zhao, Weihong; Huang, He

doi:10.1038/bmt.2017.64

Cited by 7 publications

(10 citation statements)

References 15 publications

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“…CD19-CAR T cells have been previously described to infiltrate immune privileged sites beyond the CNS, documented by, for example, a recent case report on bilateral retinal detachment after CD19-CAR T-cell therapy in a patient with retinal infiltration 19 and by the efficacy of CD19-CAR T cells in testicular CD19 + leukemia. [20][21][22] In addition to local immune escape, mechanisms of insufficient CAR T-cell persistence may have led to relapse in our patient. The possible overlap and rapid evolvement of systemic leukemia after local relapse limit definitive mechanistic conclusions in our case.…”

Section: Discussionmentioning

confidence: 86%

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

Willier¹,

Raedler²,

Blaeschke³

et al. 2020

J Immunother Cancer

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BackgroundRelapsed/refractory B-precursor acute lymphoblastic leukemia (BCP-ALL) remains a major therapeutic challenge in pediatric hematology. Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable initial response rates in BCP-ALL patients, while long-term leukemia control rate is only about 50%. So far, main mechanisms of BCP-ALL relapse after CD19-CAR T-cell therapy have been either insufficient CAR T-cell persistence in vivo or loss of surface CD19.Case ReportHere, we report an exceptional presentation of BCP-ALL relapse in the eye during the systemic control through CAR T-cell therapy. We report a case of fatal intraocular relapse in a pediatric patient with pro-B-ALL after initial response to CD19-CAR T-cell therapy. One month after CD19-CAR T-cell therapy, remission was documented by bone marrow aspirate analysis with absence of CD19+ cells and CD19-CAR T cells could be detected in both peripheral blood and bone marrow. At the same time, however, the patient presented with progressive visual disturbance and CD19+ cells were found within the anterior chamber of the eye. Despite local and systemic therapy, ocular relapse led to BCP-ALL dissemination and systemic relapse within weeks. The eye represents a rare site for local manifestation of BCP-ALL, but isolated intraocular relapse is a clinically unreckoned presentation of BCP-ALL in the era of CD19-CAR T cells.ConclusionDuring systemic control of BCP-ALL through CD19-CAR T cells, relapse can emerge in the eye as an immune-privileged organ. Ocular symptoms after CD19-CAR T-cell therapy should guide the clinician to elucidate the etiology in a timely fashion in order to adjust leukemia treatment strategy. Both, local immune escape as well as insufficient CAR T-cell persistence may have contributed to relapse in the reported patient. Mechanisms of relapse in an immune desert under CAR T-cell therapy require future clinical and experimental attention. In particular, ocular symptoms after CAR T-cell therapy should be considered a potentially early sign of leukemia relapse.

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Section: Discussionmentioning

confidence: 86%

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

Willier¹,

Raedler²,

Blaeschke³

et al. 2020

J Immunother Cancer

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“…Although CAR‐T cells have mostly been used to treat bone marrow relapse, CAR‐T therapy has been effective for CNS leukemia, and CAR‐T cells have been observed beyond the blood‐brain barrier. Similarly, the control of testicular relapse with CAR‐T cells and their penetration of the blood‐testis barrier have been reported 78‐80 . If other studies confirm CAR‐T therapy to be effective for treating testicular relapse, this approach will be quite attractive because CAR‐T cells can control both medullary and extramedullary disease and are expected to have less gonadal toxicity.…”

Section: Management Of Testicular Relapsementioning

confidence: 85%

Testicular involvement of acute lymphoblastic leukemia in children and adolescents: Diagnosis, biology, and management

Nguyen

Terao

Green

et al. 2021

Cancer

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Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. The testes were long considered pharmacologic sanctuary sites, presumably because of the blood‐testis barrier, which prevents the entry of large‐molecular‐weight compounds into the seminiferous tubule. Patients with testicular involvement were historically treated with testicular irradiation or orchiectomy. With the advent of contemporary intensive chemotherapy, including high‐dose methotrexate, vincristine/glucocorticoid pulses, and cyclophosphamide, testicular leukemia present at diagnosis can be eradicated, with the risk of testicular relapse being 2% or lower. However, the management of testicular leukemia is not well described in the recent literature and remains relevant in low‐ and middle‐income countries where testicular relapse is still experienced. Chemotherapy can effectively treat late, isolated testicular B‐cell ALL relapses without the need for irradiation or orchiectomy in patients with an early response and thereby preserve testicular function. For refractory or early‐relapse testicular leukemia, newer treatment approaches such as chimeric antigen receptor–modified T (CAR‐T) cell therapy are under investigation. The control of testicular relapse with CAR‐T cells and their penetration of the blood‐testis barrier have been reported. The outcome of pediatric ALL has been improved remarkably by controlling the disease in the bone marrow, central nervous system, and testes, and such success should be extended globally. Lay Summary Acute lymphoblastic leukemia (ALL) in children and adolescents can involve the testes at diagnosis or upon relapse. Modern intensive chemotherapy has largely eradicated testicular relapse in high‐income countries. Consequently, most current clinicians are not familiar with how to manage it if it does occur, and testicular relapse continues to be a significant problem in low‐ and middle‐income countries that have not had access to modern intensive chemotherapy. The authors review the historical progress made in eradicating testicular ALL and use the lessons learned to make recommendations for treatment.

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“…Studies have shown persistence of isolated microscopic testicular leukaemia after completion of initial treatment which is disconcerting 9. The testes is considered an immune sanctuary which likely contributes to its predisposition as a site for extramedullary recurrence after hematopoietic stem cell transplant 11 12. Several mechanisms have been proposed to explain this including the immunological tolerance of the testicular microenvironment and the presence of specific growth promoting factors that enhance tumour cell proliferation, such as lymphocyte growth factors (IL like-1) 13.…”

Section: Discussionmentioning

confidence: 99%

“…It is also important to differentiate relapse from primary testicular tumours such as spermatocytic seminoma in elderly patients. Current treatment modalities for patients with ITR include orchiectomy, local irradiation, systemic chemotherapy or a combination of these modalities 12 17. Successful management with orchiectomy alone has been reported although not widely accepted 18.…”

Section: Discussionmentioning

confidence: 99%

“…Systemic submicroscopic disease has been identified in patients presenting with apparent ITR and is the rationale for intensified systemic treatment 20. Novel therapies such as chimeric Ag receptor-modified T cell therapy has been shown to successfully treat ITR with minimal side effects and could be investigated further 12. There are proposals to omit radiation therapy as systemic therapy becomes more effective but it remains to be further validated 3.…”

Section: Discussionmentioning

confidence: 99%

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Isolated testicular recurrence of B cell acute lymphoblastic leukaemia in an adult: rare case

et al. 2019

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An 80-year-old man who was previously diagnosed with Philadelphia+ B cell-acute lymphoblastic leukaemia (B-ALL) in remission post-allogeneic matched unrelated donor peripheral blood stem cell transplant. Five years later, he was found to have unilateral testicular relapse of Philadelphia+ B-ALL proven by pathology after radical orchiectomy. Bone marrow aspirate and biopsy did not show evidence of leukaemia. Patient was treated with adjuvant radiation therapy and started on dasatinib 50 mg daily. Given his age and absence of disseminated acutelymphoblastic leukaemia (ALL), no adjuvant chemotherapy was utilised. He is monitored with monthly PCR studies. At 1-year follow-up, no findings suggestive of recurrence of ALL have been identified and the patient is maintained on the dasatinib. Although isolated testicular recurrence is common among paediatric population, it is a rare event among adults as it is considered an immunological sanctuary for cancer cells.

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Successful chimeric Ag receptor modified T cell therapy for isolated testicular relapse after hematopoietic cell transplantation in an acute lymphoblastic leukemia patient

Cited by 7 publications

References 15 publications

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

Leukemia escape in immune desert: intraocular relapse of pediatric pro-B-ALL during systemic control by CD19-CAR T cells

Testicular involvement of acute lymphoblastic leukemia in children and adolescents: Diagnosis, biology, and management

Isolated testicular recurrence of B cell acute lymphoblastic leukaemia in an adult: rare case

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