3. Discussion
GVHD is a clinicopathological syndrome caused by the mismatch of HLA recognized by donor-derived T cells through T cell receptor α β, thus attacking the organs and tissues of patients[6]. CAR-T therapy involves using genetic engineering technology to make allogeneic T cells specific to tumour antigens, such as CD19, rather than to all cells. Moreover, CAR-T cell therapy involves a small number of cells, which in theory induces a low rate of GVHD. However, in clinical application, we found that both haploid and non-haploid donor-derived CAR-T cell therapy can induce GVHD, and the reasons need to be further explored.
Here we describe two cases, one involving a matched-sibling donor (patient 1) and the other a haploid donor (patient 2).The incidence of GVHD after haploid transplantation is higher than with matched-sibling donor and unrelated donor transplantation[6]. Whether CAR-T from a haploid donor is more likely to induce GVHD and cause safety concerns is an important question. The incidence of GVHD after CAR-T infusion is lower than with donor leukocyte infusion and seems to be related to the tumour load. If the tumour load is low, the incidence of GVHD also is low[7-10,12,13].At present, there is no relevant research on cGVHD after CAR-T cell therapy, only limited clinical data from some samples.
We report here that two patients had different degrees of cGVHD after donor-derived CAR-T treatment. The most serious was lung involvement. The clinical diagnosis was BOS, which mainly manifested as shortness of breath after active, intractable cough, imaging findings of gas retention, and pulmonary function suggesting obstructive pulmonary disease with restricted ventilation. Studies have shown that the mortality rate with BOS after transplantation can be as high as 80%, and the main causes of death are respiratory failure and severe infection [11]. In theory, secondary BOS after CAR-T would be similar to that after transplantation. We actively intervened in these two cases at an early stage, including strengthening immunosuppressant, FAM regimen, TKI, and auxiliary cell therapy. Fortunately, the dyspnoea and lung function of the two children were significantly improved and recovered. They were in a state of continuous remission without a second transplant.
Donor-derived CAR-T cell therapy adds to the toolkit clinicians can use to prevent recurrence after transplantation and provides an effective treatment option for patients. However, there is a real risk of GVHD caused by donor-derived CAR-T. How to increase and extend the effect of CAR-T treatment while reducing the incidence and mortality of GVHD are being explored. In the near future, more effective and lasting off-the-shelf CAR-T products are anticipated.