**3. Preclinical investigations and clinical applications**

The current clinical and preclinical successes of cellular immunotherapy represent a remarkable point in cancer management, which also underscore the consequence of decoding the underlying tumor immunology [36, 134, 135]. Accumulating evidence has indicated the safety and effectiveness of cellular immunotherapy in recognizing and eliminating transformed cancer cells during various hematologic malignancies whereas those upon metastatic solid tumors are challenging and unsatisfactory [135, 136].

Generally, according to ClinicalTrials.gov (https: //www.clinicaltrials.gov/) website, a total number of 4377 trials upon tumors by immunotherapy have been registered by the end of September, 2021. Of the aforementioned trials, there are 2463 in North America, 1089 in Europe and 834 in East Asia, respectively (**Figure 1**). As shown in **Figure 1**, among the indicated registered trials, there are 3944 interventional trials including 96 trials in early phase 1 stage, 957 in phase 1 stage, 776 in phase 1/2 stage, 1555 in phase 2 stage, 59 in phase 2/3 stage, 260 in phase 3 stage and 29 in phase 4 stage. In details, lymphoma (512 trials), leukemia (331 trials) and non-Hodgkin lymphoma (281 trials) are the top three indicates among hematologic malignancies, while lung neoplasms (822 trials), neuroectodermal tumors (751 trials) and digestive system neoplasms (696 trials) are the top three indicates among solid tumors (**Figure 1**). For instance, 26 trials of NK cell-based immunotherapy have been registered for a series of metastatic or recurrent tumor administration such as acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia, liver cancer, breast cancer, non-small cell lung cancer (NSCLC), pancreatic cancer, ovarian cancer, cervical cancer, tongue cancer and esophageal cancer. Also, a number of 16 CAR-T-based immunotherapy (e.g., CD19, CD22, HER2, mesothelin, PSCA, MUC1, GPC3, BCMA, SLAMF7) has also been carried out for both hematological malignancies (e.g., relapsed/refractory multiple myeloma, acute lymphocytic leukemia and refractory indolent adult non-Hodgkin lymphoma) and solid tumors (e.g., advanced lung cancer, colon cancer, esophageal carcinoma, pancreatic cancer, prostate cancer, gastric cancer and hepatic carcinoma). For instance, we recently took advantage of the CD22, CD19–22 CAR-T therapy in patients with refractory or relapsed (r/r) B acute lymphoblastic leukemia (B-ALL) and confirmed the sustained remission after sequential treatment [98–100, 137, 138]. Additionally, other cancer immunotherapy has also been taken into practice including PD-1 (NCT02843204), TCR-T therapy (NCT03778814), DC-CIKs (NCT03190811, NCT01783951), Bevacizumab (NCT02857920).

*Cancer Immunotherapy and Cytotoxicity: Current Advances and Challenges DOI: http://dx.doi.org/10.5772/intechopen.105184*

#### **Figure 1.**

*The overview of registered cancer immunotherapy worldwide.*

As to preclinical investigations, immunotherapy has also acted as an "off-the-shelf" strategy and a promising candidate for clinical evaluation of cancer [21, 25, 102]. For example, Sommer *et al* reported the incorporation of allogeneic BCMA-CAR-Ts and CD20 mimotope-based intra-CAR off switch for conferring lymphodepletion resistance and reducing GvHD potential with the aid of the transcription activator-like effector nuclease (TALEN)-based gene editing. Notably, the CAR-T-based immunotherapy induced sustained antitumor responses and the cells maintained intrinsic phenotype and potency after scale-up manufacturing [139]. Recently, we reported the high-efficient generation of NK cells from peripheral blood with considerable killing activity upon K562 cells and summarized the latest updates upon allogeneic NK cell- and CAR-NK cellbased immunotherapy as well [21, 45]. Interestingly, we also found the delay of disease progression and improvement of leukemic hematopoietic microenvironment (LHME) in AML mouse models by blocking the migration of regulatory T cells (Treg) [140, 141].
