Clinical uses of GM-CSF, a critical appraisal and update

Figures & data

Figure 1 GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect.

Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte.

Table 1 Recent trials using GM-CSF in patients with renal cell carcinoma

Author	Population	Immune therapy	Dose of GM-CSF	Outcomes	Toxicities (most common)
Correale et al 2005	19 Metastatic RCC	IL-2 0.5 MIU BID SQ D 6–15	150 μg/day SQ D 1–5	PR: 4/19 SD: 11/19 mTTP = 9 months 2 year OS 42% 3 year OS 26%	Bone pain, asthenia, and fever
Verra et al 2003	59 Progressive RCC	IL-2: 4 MIU/m^2 SQ INF-α :5MIU SQ × 12 days every 3 wks	2.5 μg/kg SQ D 1–12	CR: 5/59 PR: 6/59 mOS: 9.5 mos.	Flu-like symptoms, transient LFT elevations
Lissoni et al 2003	25 Metastatic RCC	IL-2: 6 MIU/day SQ 6 D/wk × 4 wks 2 cycles (21-day intervals) Maintenance: 6 days/ month until progression	13 patients also received GM-CSF 0.3 μg/kg D 1–3 each week of Il-2	IL-2 alone PR: 3/13 SD: 8/13 IL-2 + GM PR: 3/12 SD: 6/12	More asthenia occurred in the IL-2 + GM group
Smith et al 2003	21 (13 with metastatic RCC)	IL-2: 72,000 IU/kg TID × on D 2–6 and D16–20 ± GM-CSF	125 or 250 μg/m^2/day SQ D 1–7 and D 15–21	No PR or CR SD: 4/13 with RCC	Grade 3 confusion in 4 pts (3 on IL-2 alone)
Schmidinger et al 2001	55 Metastatic RCC	IL-2: 4.5 MU day 1–4 wks. 3 and 6 INF-γ: 100 μg TIW wks 1 and 4	400 μg SQ D 1–5 weeks 2 and 5	CR: 1/53,. PR: 4/53 SD: 14/53 mOS: 12 mos	No toxicities greater than grade 2
Westermann et al 2001	10 Stage IV RCC Pilot study	IL-2: 4 MU/m^2 SQ and INF-α: 5 MIU/m^2 SQ multiple dosing schedules	5 μg/kg SQ D 1 + 4 week 1 D 1, 3, 5 week 2 D 1, 3, 5 weeks 3–5 D 1, 3, 5 weeks 7–9	PR 2/10 1/10 mixed response	One grade 3 fever No other grade 3–4 toxicities
Tate et al 2001	13 Metastatic RCC, Phase I	IL-6 1, 5, or 10 μg/kg/day D 1–14	3 μg/kg/day D1–14	No responses	DLT: thrombocytosis and hyperbilirubinemia
De Gast et al 2000	18 11 RCC 7 melanoma Phase I	IL-2: 1, 4, or 8 MIU/m^2, and INF-α: 5 MIU SQ × 12 days every 3 wks	2.5 or 5 μg/kg/day SQ	CR: 3/11 SD: 5/11	DLT: fever with chills, hypotension, fluid retention
Ryan et al 2000	20 Metastatic RCC	IL-2: 11 MIU SQ D1–4 weekly INF-α: 10 MIU SQ 2 days/week c-RA 1 mg/kg daily orally for 4 weeks	1.25 μg/day SQ D 1–14	PR: 1 SD: 3 1-year survival rate: 48%	Grade 3 fever, fatigue, anorexia mucositis, and dermatitis One on-study death
Hotton et al 2000	16 pts with RCC and pulmonary metastases	IL-2: 1.5, 2.25, or 4.5 MIU/m^2/day 96 h CIV D 1–4, 8–11, and 15–18	1.25, 2.25, or 2.5 g/kg/day SQ D 8–19	14 evaluable 0/14 had ≥50% shrinkage of total tumor burden nor reduction in pulmonary metastases	Grade 3–4 toxicities: lymphopenia, thrombocytopenia, elevated PT, thrombosis, hypotension, hypocalcemia, hyperglycemia, pain, constipation Grade 5: neurologic

Abbreviations: c-RA, cis-retinoic acid; CR, complete response; D, days; INF-α, interferon alpha; INF-γ, interferon gamma; OR, overall response; PR, partial response; pt, patient; SQ, subcutaneous; IL-2, interleukin 2; PR, partial response; mOS, median overall survival; LFT, liver function test; wks, weeks; mTTP, median time to progression; CIV, continuous intra-venous infusion; PT, prothrombin time.

Table 2 GM-CSF-containing regimens in patients with malignant melanoma

Author	Population	Concurrent therapy	Dose of GM-CSF	Outcomes	Toxicities (most common)
Lutzky et al 2003	11	Thalidomide: intra-patient dose escalation 50–400 μg PO daily	125 μg/m^2 SQ daily × 14 days	3 alive without recurrent disease	Most common: fatigue, dizziness, somnolence, constipation
Weber et al 2005	31	Temozolamide: days 1–5 INFα-2b: days 6–17 IL-2: days 6–17	125 μg/m^2 SQ days 6–17	CR: 4 PR: 4 SD: 7 mOS: 15.9 mos	SAEs in 7 patients Most common toxicity: flu-like symptoms
De Gast et al 2003	74	Temozolamide: days 1–5 INFα-2b: days 6–17 IL-2: days 6–17 Repeated every 22 days in stable/ responding pts	2.5 μg/kg SQ days 6–17	CR: 4 s PR: 19 SD: 13 mOS: 252 day	DLT: thrombocytopenia Grade 3–4 lymphopenia was observed All patients developed flu-like syndrome
Groenewegen and de Gast 1999; Groenewegen et al 2002	32	DTIC: day 1 IL-2: days 6–17 INFα-2b: days 6–17	2.5 μg/kg SQ days 2–12	CR: 4 PR: 6 mOS: 8 mos	Treatment was well tolerated
Janik et al 2001	28	Topotecan: 1.5 mg/m^2 daily x 5 days Cycle repeated every 21 days	250 μg/m^2 SQ QD post CHT 250 μg/m^2 SQ BID × 5 D prior to CHT; or none	CR: 0 PR: 1	Treatment was well tolerated
Ravaud et al 2001	32	A: None B: DTIC 800 mg/m^2 D 1 21-day cycles Cross-over from A to B allowed for non- response/progression	A: 5 μg/kg BID SQ × 14 D B: 5 μg/kg BID SQ D2-19, 21-day cycles	Best response was SD: A: 0 B: 3 OS A: 6.3 months B: 7.3 months	Dose alteration due to toxicity in 20% A and 4.7% B Grade 3 or 4 toxicity occurred in 40% A and 76.5% B
Gajewski and Flickinger 2000	7	Cisplatin, DTIC: D1 IL-2: D 8–14 INF-α: D 8,10,12,14 28 day cycles	5 μg/kg SQ D 2–7	CR: 1 PR: 1 MR: 2	Treatment was well tolerated
Gibbs et al 2000	72	Temozolamide: D1–5 Cisplatin: D 1–3 IL-2: D 1–4 INF-α: D 1–5 28-day cycles	250 μg SQ days 6–25	CR: 1 PR: 11 mOS: 11 mos	Significant toxicity with grade 2 and 4 thrombocytopenia and renal impairment
Vaughan et al 2000	19	Cisplatin: D 1–3 DTIC: D 1–3 Tamoxifen: daily IL-2: D 6–10, 17–21 INFα-2b: days 6–10 and 17–21 28-day cycles	450 μg/m^2 SQ D 4,5,15,16 or 450 μg/m^2 SQ D 4,5,15,16 and 225 μg/m^2 SQ D 6–10, 17–21 or 450 μg/m^2 SQ D 4–10, 15–21	OR: 6 CR: 2 mOS: 6.2 mos.	Grade 3–4 toxicities: bone marrow suppression, hypotension, pulmonary edema, confusion, and increased serum creatinine
Schachter et al 1998	40	INF-α: days 1,3,5 Carmustine: day 8 Cisplatin: days 8–10 DTIC: days 8–10 Tamoxifen: daily 21-day cycles	20 μg/m^2/day SQ × 7 days following chemotherapy	CR: 9 PR: 11 Survival benefit in responders: 22 mos. vs 8 mos.(p = 0.0001)	Treatment was well tolerated

Abbreviations: bid, twice daily; TIW, 3 times weekly; DTIC, dacarbazine; INF-α, interferon alpha; IL-2, interleukin 2; PD, progressive disease; PO, orally; PR, partial response; pt, patient; OR, overall response; mOS, median overall survival; SQ, subcutaneously; LFT, liver function test; wks, weeks; CHT, chemotherapy; D, days; DLT, dose-limiting toxicity; SAEs, serious adverse events.

Table 3 Clinical trials using GM-CSF transduced tumor cells as vaccines

Authors	Tumor type	Clinical results
Slingluff et al 2003	Melanoma Randomized comparison of multipeptide vaccine either in emulsion with GM-CSF or pulsed on monocytoid DCs	– Overall immune responses, including T-cell responses were superior in the GM-CSF arm, compared to the DC arm – Helper T-cell responses were detected and correlated with T-cell reactivity to the melanoma peptides – 2 PR in the GM-CSF arm, 1 in the DC arm. -2 SD in the GM-CSF arm and 1 in the DC arm – mOS:14.8 months for patients in the GM-CSF arm and 6.2 months for the DC arm.
Nelson et al 2000	Renal cell carcinoma	– Increase in DTH response against autologous tumor cells – 1 PR
Simons et al 1999;Simons and Sacks 2006	Prostate cancer	– Increase in DTH response – Induction of tumor specific T-cell and B-cell responses
Kusumoto et al 2001	Melanoma	– Increase in DTH response – Increase in melanoma specific CTLs in most patients
Soiffer et al 1998; Soiffer et al 2003	Melanoma	– Increase in DTH response – Eosinophilia – TILs highly cytotoxic – 1 CR, 1PR, 1MR, 3 minor responses
Salgia et al 2003	Non-small cell lung Cancer	– Increase in DTH response – T-cell and plasma cell infiltration of metastatic sites – 5 SD, 1 mixed response
Jaffee et al 2001	Pancreatic cancer	– Increase in DTH response – Increased systemic GM-CSF levels – 2/5 patients receiving highest cell dose >25 months in CR

Abbreviations: DTH, delayed type hypersensitivity; PR, partial response; CTLs, cytotoxic T lymphocytes; TILs, tumor infiltrating lymphocytes; MR, minor response; SD, stable disease; mOS, median overall survival; CR, complete response.

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