Chimeric Antigen Receptor (CAR) T-Cell Therapy for Patients with Lung Cancer: Current Perspectives

Figures & data

Figure 1 Generations of chimeric antigen receptors. Chimeric antigen receptors consist of a targeting moiety (most commonly an scFv as illustrated here), a spacer/hinge, transmembrane domain and a signaling endodomain. Antigen recognition is direct provided that a target cell (here designated as antigen-presenting cell) expresses the target antigen on the cell surface. In first generation (1G) CARs, the endodomain contains an ITAM (immunoreceptor tyrosine-based activation motif)-containing activating module. Most commonly CD3 zeta is used for this purpose since each monomer contains 3 ITAMs. Second generation (2G) CARs contain a co-stimulatory domain placed upstream of CD3 zeta and most commonly derived from CD28 or 4–1BB. Third generation (3G) CARs contain two complementary co-stimulatory units while armored CARs produce a cytokine such as IL-12 or IL-18.

Table 1 Clinical Trials Evaluating CAR T-Cell Immunotherapy of Lung Cancer

Ref	Year	Institution/Sponsor	Clinical Trial Register	Target	CAR Gen.	Disease	No. Treated	Conditioning	Cell Product and Dose	Clinical Outcome	Toxicity (>Grade 3)	Survival
[85]	2011	UPenn	NCT01355965	MSLN	2G: 41BB	MSLN -expressing cancer	2	Nil	1 to 10×10[8] cells x 3 infusions (mRNA transfected)	1PR	1 anaphylaxis	Not known
[86]	2012	NCI	NCT01583686	MSLN	Not known	MSLN -expressing tumors including lung cancer	Not known	Cy/Flu + IL-2	Not known	Terminated due to slow accrual 1/15 SD; 14/15 PD	Not known	Not known
[87]	2015	MSKCC	NCT02414269	MSLN	2G: CD28	Pleural cancers	20 14 in cohort 3 evaluable for efficacy	Nil (3) Cy (3) Cy + anti-PD-1 (14)	3x10[5]-1x10[7]/Kg	14% CR 36% PR 29% SD	0% CRS 0% ICANS	Not known
N/A	2015	PersonGen Bio-Therapeutics (Suzhou) Co. Ltd.	NCT02587689	MUC1	Not known	Multiple including NSCLC	Not known	Not known	Not known	Trial status unknown	Not known	Not known
N/A	2015	Southwest Hospital China	NCT02349724	CEA	2G: CD28	Multiple including lung cancer Colorectal cancer data published[88]	Not known	Not known	Not known	Trial status unknown	Not known	Not known
N/A	2015	Chinese PLA General Hospital	NCT02580747	MSLN	Not known	Multiple including lung cancer	Not known	Not known	Not known	Trial status unknown	Not known	Not known
[89]	2016	Chinese PLA General Hospital	NCT01869166	EGFR	2G: 41BB	NSCLC	11	Nil, Cy alone or Cy with additional cytotoxic drugs	up to 2.5×10[7] CAR T-cells/ kg (median dose 0.97x10[7]/kg)	18% PR 45% SD	0% CRS 0% ICANS	Responses lasted 2–8m
N/A	2016	Zhi Yang	NCT02713984	HER2	Not known	Multiple, including lung cancer	Not known	Not known	Not known	Study withdrawn due grade 4 CRS and interstitial pneumonia	Not known	Not known
[90]	2016	Fred Hutchinson Cancer Center	NCT02706392	ROR1	2G: 41BB	Multiple, including NSCLC	4	Cy/Flu	3.3 x 10[5] to 1 x10[6]/kg	2SD Study terminated due to slow accrual	Not known	Not known
N/A	2016	Shanghai International Medical Center	NCT02862028	ErbB family	Armored with PD1 antibodies	Multiple including lung cancer	Not known	Not known	1–5 x 10[7]/kg x 2 cycles	Trial status unknown	Not known	Not known
[88]	2017	Third Military Medical University	NCT02349724	CEA	2G: CD28	Lung cancer and other CEA+ cancers	10	Cy	1 x 10[5] to 1 x10[8]/kg	70% SD	0% CRS 0% ICANS	20% SD at 30 week follow up
[91]	2017	Shanghai Cell Therapy Research Institute	NCT03182816	EGFR	2G: 41BB PiggyBac transposon mediated gene transfer	Multiple including lung cancer	9 lung cancer	Cy	1 x 10[6] to 3 x 10[6]/kg	1/9 PR 6/9 SD	1/9 grade 3 fever. No other grade 3 toxicities
N/A	2017	Second Affiliated Hospital of Guangzhou Medical University	NCT03198052	Multiple	Not known	Multiple including lung cancer	Not known	Not known	1 x10^6 to 1 x10^7/kg x 3 cycles	Not known	Not known	Not known
N/A	2017	Second Affiliated Hospital of Guangzhou Medical University	NCT03198546	Glypican-3	TGF-b targeting CAR which secretes IL-7 and CCL19	Hepatocellular cancer and NSCLC	Not known	Not known	Not known	Not known	Not known	Not known
[92]	2017	Sun Yat-sen University	NCT03330834	PD-L1	2G: 41BB	NSCLC	Not Known	Cy/Flu	1 x10[6] to 6 x10[5]/kg (3 doses over 7 days)	Study terminated due to toxicity (see text)	Not known	Not known
N/A	2017	UPenn	NCT03054298	MSLN	2G: 41BB	Multiple including lung adeno-carcinoma IV, IP and intrapleural routes	Not known	Nil or Cy	1–3 x10[7] to 1–3 x10[8]/m[2]	Not known	1 patient death due to respiratory failure (summarized in[24])	Not known
N/A	2017	Yu Fengiei	NCT03060343	PD-L1; CD80 CD86	Not known	NSCLC	Not known	Not known	1 x10[5] to 1 x10[7]/kg	Not known	Not known	Not known
[93]	2018	Chinese PLA General Hospital	NCT01935843	HER2	2G: 41BB	Multiple, including NSCLC (no NSCLC patients reported as yet)	11	Cy/ nab-paclitaxel	Median dose 2.1x10[6]/Kg x 1–2 cycles	9% PR 45% SD	0% CRS 0% ICANS	Med PFS 4.8m
[94]	2018	Amgen	NCT03392064	DLL3	Not known	SCLC	5	1PR 2SD	3.3–10[5]/Kg x 1–2 cycles	Suspended	0% CRS 0% ICANS	Med PFS 3.7m
[95]	2018	The First Affiliated Hospital of Guangdong Pharmaceutical University	NCT03525782	MUC1	PD1 knockout	NSCLC	20	Not known	1–4 cycles of treatment	11 SD	0% CRS 0% ICANS	Not known
N/A	2018	Shenzen BinDeBio Ltd.	NCT03638206	Multiple	Not known	Multiple including lung cancer	Not known	Cy/Flu	Not known	Trial status unknown	Not known	Not known
N/A	2018	Baylor College	NCT03740256	HER2	Combined with intratumoral oncolytic adenovirus	Multiple including lung cancer	Not known	Not known	Not known	Not known	Not known	Not known
[96]	2019	UPenn	NCT02159716	MSLN	2G: 41BB	Multiple including malignant pleural mesothelioma	15	Nil or Cy	1–3x10[7]or 1–3x10[8]/m[2] cells	73% SD	0% CRS 0% ICANS	Med PFS 2.1m
[97]	2019	Tmunity Therapeutics	NCT04025216	MUC1 Tn	2G: 41BB	Multiple including NSCLC	6	Nil or Cy/Flu	1–6 x 10[7]/kg	3SD	0% CRS 0% ICANS	Not known
[98]	2019	Sun Yat-sen University	NCT04153799	EGFR	Armored with CXCR5	NSCLC	11	Not known	0.5–5x10[6]/Kg	2 PR 5SD	Not known	Not known
N/A	2019	Shenzhen Geno-Immune Medical Institute	NCT03356808	Multiple	Not known	Lung cancer	Not known	Not known	1–10 x 10[6]/kg	Not known	Not known	Not known
N/A	2020	Chongqing Precision Biotech Co. Ltd	NCT04348643	CEA	Not known	Lung cancer and other CEA+ cancers	Not known	Not known	1–3 IV doses	Not known	Not known	Not known
N/A	2020	Wuhan Union Hospital	NCT04489862	MSLN	Armored with anti-PD1 nanobodies	NSCLC and mesothelioma	Not known	Cy	1x10[5]-3x10[6]/Kg	Not known	Not known	Not known
[99]	2020	MSKCC	NCT04577326	MSLN	2G: CD28 (1XX zeta domain) armored with PD1 dominant negative receptor. Intrapleural delivery	Mesothelioma		Cy	Up to 3x10[7]/Kg	Not known	1 fatal SAE causing temporary pause to recruitment in 2022	Not known
N/A	2021	Second Affiliated Hospital of Guangzhou Medical University	NCT04952272	Not known	Armored with OX40 scFv. Combined with intra-tumoral drug-eluting beads and CpG-ODN	Multiple including lung cancer	Not known	Not known	Not known	Not known	Not known	Not known
N/A	2021	Second Affiliated Hospital of Guangzhou Medical University	NCT05060796	EGFR	Armored with CXCR5	NSCLC	Not known	Not known	0.5–5x10[6]/Kg	Not known	Not known	Not known
N/A	2021	Beijing Immunochina Medical Science and Technology Company	NCT05117138	Not known	Not known	Multiple including NSCLC	Not known	Not known	Not known	Not known	Not known	Not known
N/A	2021	PersonGen Bio-Therapeutics (Suzhou) Co. Ltd.	NCT04864821	B7-H3	Not known	Multiple including NSCLC	Not known	Not known	Not known	Not yet recruiting
N/A	2021	SOTIO LLC	NCT05120271	Glypican-3	2G: 41BB Glutamic oxaloacetic transaminase 2 armoring[41]	Multiple including NSCLC	Not known	Cy/Flu	Three dose levels during dose escalation	Not known	Not known	Not known
N/A	2022	PersonGen Bio-Therapeutics (Suzhou) Co. Ltd.	NCT05190185	B7-H3	Not known	Multiple including NSCLC	Not known	Not known	1x10[6]-1x10[8]/Kg	Not known	Not known	Not known
[100]	2022	Poseida Therapeutics	NCT05239143	MUC1-C	Allogeneic CAR T-cells TCRB knock out by Cas-Clover Piggy-Bac gene delivery	Multiple including NSCLC	3	Cy/Flu ± rituximab	0.5–15x10[6]/Kg	Not known	0% CRS 0% GvHD	Not known
N/A	2022	Second Affiliated Hospital of Guangzhou Medical University	NCT05341492	EGFR/ B7-H3	Not known	Lung cancer and triple negative breast cancer	Not known	Not known	2x10[6]/Kg	Not known	Not known	Not known
N/A	2022	UNC Lineberger Comprehensive Cancer Center	NCT05620342	GD2	Armored with IL-15 and inducible caspase 9	Lung cancer	0	Not known	Not known	Not yet recruiting
[101]	2022	Lyell Immunopharma, Inc.	NCT05274451	ROR1	Genetically and epigenetically reprogammed CAR T-cells	Multiple including NSCLC	Not known	Cy/Flu	Not known	Not known	Not known	Not known
N/A	2023	Legend Biotech USA	NCT05680922	DLL3	Not known	SCLC and large cell neuroendocrine lung cancer	0	Not known	Not known	Not yet recruiting
[102]	2023	A2 Biotherapeutics Inc.	NCT05736731	CEA and HLA-A2 loss	Logic gated CAR-T employing LIR-1 based inhibitor CAR	Multiple including NSCLC	0	Not known	Not known	Not yet recruiting

Abbreviations: 2G, 2nd generation; CEA, carcinoembryonic antigen; CR, complete response; CRS, cytokine release syndrome; Cy, cyclophosphamide; EGFR, epidermal growth factor receptor; FAP, fibroblast activation protein; Flu, fludarabine; ICANs, immune cell-associated neurotoxicity syndrome; IL, interleukin; IP, intraperitoneal; IV, intravenous; MSKCC, Memorial Sloan Kettering Cancer Center; MSLN, mesothelin; N/A, not applicable; NCI, National Cancer Institute; NSCLC, non-small cell lung cancer; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; TGF-b, transforming growth factor b; UPenn, University of Pennsylvania.

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