Mocht u kanker-actueel de moeite waard vinden en ons willen ondersteunen om kanker-actueel online te houden dan kunt u ons machtigen voor een periodieke donatie via donaties: https://kanker-actueel.nl/NL/donaties.html of doneer al of niet anoniem op - rekeningnummer NL79 RABO 0372931138 t.n.v. Stichting Gezondheid Actueel in Amersfoort. Onze IBANcode is NL79 RABO 0372 9311 38   

Helpt u ons aan 500 donateurs?

16 november 2017: Bron: Nat Rev Clin Oncol. Author manuscript; available in PMC 2016 Jun 22.

Lymfklierkanker is er in verschillende vormen en sommige vormen ook gerelateerd aan vormen van leukemie. Bv. ziekte van Hodgkin is anders dan Non-Hodgkin maar heeft uiteraard wel verschillende kenmerken. Zo ook zijn er onder vormen van leukemie verschillende vormen, ieder met eigen karakteristieken. Gemeenschappelijk hebben deze vormen van kanker dat ze sterk gerelateerd zijn aan de 'conditie' van het immuunssyteem en de actieve T-cellen. En er wordt al heel lang gezocht naar de beste vorm van immuunstimulerende medicijnen en behandelingen bij deze vormen van kanker met zoals ze dat noemen kwaadaardige lymfoïden.

Zo heeft het zogeheten anti-CD20 monoklonale antilichaam rituximab bij de behandeling van vormen van lymfklierkanker en vormen van leukemie veel succes bij deze vormen van kanker. In feite is rituximab ook een vorm van immuuntherapie. Sinds de goedkeuring door de FDA van rituximab in 1997 zijn er de afgelopen jaren wel ook weer verschillende nieuwe vormen van immuunstimulatie onderzocht die het vermogen om de T-cellen te stimuleren en nog gerichter de kankercellen aan te kunnen vallen. En met succes lijkt het. 

immuuntherapie bij lymfklierkanker


Rekening houdend met de veelbelovende resultaten uit de praktijk van deze nieuwe immunotherapiebenaderingen, heeft de FDA onlangs een 'doorbraak'-aanduiding toegekend aan drie nieuwe immuunstimulerende behandelingen met verschillende mechanismen.

Ten eerste is chimere antigeenreceptor (CAR) -T-celtherapie veelbelovend voor de behandeling van een recidief van ALL - acute lymfoblastische leukemie bij volwassenen en kinderen.

Ten tweede is blinatumomab, een zogeheten anti lichaam met bispecifieke T-cel stimulatie (BiTE®), inmiddels goedgekeurd voor de behandeling van volwassenen met Philadelphia-chromosoom-negatieve gerecidiveerde en / of refractaire B-precursor ALL.

Ten derde heeft immuuntherapie met het zogeheten anti-PD medicijn nivolumab, uitstekende resultaten laten zien voor de behandeling van het Hodgkin-lymfoom nadat een recidief optrad na de behandeling met autologe stamceltransplantatie en brentuximab-vedotine. 

Er zijn drie studies die recent zijn gepubliceerd die ik onder jullie aandacht wil brengen:

Deze studie: The landscape of new drugs in lymphoma bespreekt alle vormen van medicijnen bij vormen van lymfklierkanker.

Kernpunten uit deze studie zijn:

  • De beschikbaarheid van nieuwe kleinmoleculaire remmers en immuuntherapieën heeft het landschap van medicijnontwikkeling bij lymfomen veranderd.
  • De meest effectieve remmers van kleine moleculen zijn gericht op B-cel-receptor-signalering, PI3K-signalering en het BCL2-eiwit.
  • Meerdere immunotherapeutische studies hebben veelbelovende klinische activiteit aangetoond, waaronder checkpoint remmers (anti-PD medicijnen), CAR T-cellen en bispecifieke antilichamen
  • Veel bedrijven ontwikkelen soortgelijke geneesmiddelen, die hetzelfde doel hebben, waardoor een meer gerichte strategie voor de ontwikkeling van geneesmiddelen nodig is, met prioriteit voor klinisch onderzoek.
  • Vanwege het grote aantal geneesmiddelen dat in ontwikkeling is, wordt het potentiële aantal medicijncombinaties onhandelbaar; Prioriteit moet zich richten op mechanisme-gebaseerde combinaties die potentieel veiliger en effectiever zijn.

Een andere studie is de studie: Clinical applications of genome studies waarin bepaalde biomarkers een grote rol spelen bij de aanpak van lymjfklierkanker en aanverwante vormen van kanker.

En recent is er ook een studie gepubliceerd: Novel immunotherapies in lymphoid malignancies waarin de onderzoekers de achtergrond en ontwikkeling van drie verschillende vormen van immuuntherapie bespreken aan de hand van de literatuur en de wetenschappelijke vooruitgang daarin. M.i. geeft deze studie een uitstekende analyse en maakt het werkingsmechanisme van elke individuele therapie inzichtelijk en begrijpelijk. In de studie bespreken zij ook toekomstige strategieën om deze immunotherapie verder te verbeteren door middel van verbeterde engineering, biomarkerselectie en mechanisme-gebaseerde combinaties van behandelingen. Over deze studie geef ik in dit artikel wat meer informatie.

Het volledige studierapport: Novel immunotherapies in lymphoid malignancies is onderverdeeld in verschillende hoofdstukken. Klik op de kopjes om naar de hoofdstukken te gaan. Ik heb niet altijd een vertaling gemaakt maar u kunt altijd de google translate optie gebruiken rechtsboven elk artikel.

Engineerd T-car cells

Conclusie uit dit hoofdstukje:

On the basis of promising clinical results, multiple pharmaceutical companies (such as Novartis, Juno Therapeutics, Cellular Biomedicine Group, Bellicum, Celgene/Bluebird, Kite Pharma/Amgen, Cellectis/Servier/Pfizer, Opus Bio, TheraVectys) are developing large-scale clinical-grade production of CAR T cells91. The participation of pharmaceutical companies is critical for success; however, the treatment is unlikely to be standardized in the near future owing to patent issues. Identification of a lead CAR-T-cell construct is unlikely in the absence of head-to-head trials that directly compare each construct and each method in specific disease settings. Results of larger studies of homogenously treated patients across multiple centres with detailed toxicity assessment will be essential in guiding the clinical development of this novel treatment strategy.

Hier een schema van studies met T-car cells. Nummers verwijzen naar referentieliijst onderaan dit artikel

Table 1

Clinical efficacy of second generation CAR-T-cell therapy

Disease and treating instituteNumber of patientsConditioning therapyInfused CAR T-cell doseResponse rate
Survival outcomes
ORR (%)CR (%)PR (%)SD (%)
ALL

MSKCC44,4850 22 (16* + 6) CY (1.5–3.0 g/m2) 1–3 × 106/kg NA 91 NA NA Median OS: 9 months

UPenn51 30* FLU (30 mg/m2 × 4 days)/CY (500 mg/m2 × 2 days): 13, FLU (30 mg/m2 × 4 days)/CY (300 mg/m2 × 2 days): 2, CY (440 mg/m2 × 2 days)/VP (100 mg/m2 × 2 days): 5, CVAD (CY 300 mg/m2 q12h × 3 days, vincristine 2 mg day 3, doxorubicin 50 mg/m2 day 3): 2, CY (300 mg/m2 q12h × 3 days or 1,000 mg/m2 × 1 day): 3, clofarabine 30 mg/m2 × 5 days: 1; VP (150 mg/m2 × 1 day)/Ara-C (300 mg/m2 × 1 day): 1
None: 3
0.76–14.96 × 106/kg NA 90 NA NA NA

NCI52 20* FLU (25 mg/m2 × 3 days)/CY (900 mg/m2 × 1 day) 1 or 3 × 106/kg NA 70 NA 15 RFS: 78.8% at 4.8 months

Fred Hutchinson88 7 Lymphodepleting chemotherapy 2 × 105/kg, 2 × 106/kg, or 2 × 107/kg NA 71.4 NA NA NA

CLL

UPenn45,60,61 14 (3* + 11) FLU (30 mg/m2 × 3 days)/CY (300 mg/m2 × 3 days): 3, pentostatin/CY§: 5, bendamustine§: 6 0.14–5.9 × 108 57.1 21.4 35.7 NA NA

UPenn62 23 Lymphodepleting chemotherapy 5 × 107 or 5 × 108 39 22 17 NA NA

NCI63 4* FLU (25 mg/m2 × 5 days)/CY (60 mg/kg × 2 days) + i.v. IL-2 following CAR-T-cell infusion 0.3–3 × 107/kg 75 25 50 25 NA

NCI64 4* FLU (25 mg/m2 × 5 days)/CY (60 or 120 mg/kg × 2 days) 1–5 × 106/kg 100 75 25 NA NA

MSKCC44,58 10 (8* + 2) None: 4, CY-conditioning (1.5 or 3 g/m2): 4, BR (rituximab 375 mg/m2 × 1 day, bendamustine 90 mg/m2 × 2 days): 2 0.4–1.0 × 107/kg 20 10 10 20 NA

MSKCC59 7 PCR × 6 cycles, CY (600 mg/m2) 3–30 × 106/kg 57.2 14.3 42.9 NR NA

B-NHL

NCI63 4* FLU (25 mg/m2 × 5 days)/CY (60 mg/kg × 2 days) + i.v. IL-2 following CAR-T cell infusion 0.3–3 × 107/kg 100 0 100 0 NA

NCI64 11* FLU (25 mg/m2 × 5 days)/CY (60 or 120 mg/kg × 2 days) 1–5 × 106/kg 88.9 55.6 33.3 11.1 NA

NCI65 9 FLU (30 mg/m2 × 3 days)/CY (300 mg/m2 × 3 days) 1 × 106/kg 66.7 11.1 55.6 0 NA

MSKCC67 6 BEAM conditioning and autologous SCT 5–10 × 106/kg 100 100 0 0 NA

UPenn66 8 EPOCH, CY, bendamustine, FLU/CY§ 3.7–8.9 × 106/kg (median 5.8 × 106/kg) 50 37.5 12.5 0 NA

Fred Hutchinson88 9 Lymphodepleting chemotherapy 2 × 105/kg, 2 × 106/kg, or 2 × 107/kg 66.7 11.1 55.6 NA NA
*In published report.
In reported abstract.
§Doses unknown.
PCR is pentostatin 4 mg/m2 day 1, cyclophosphamide 600 mg/m2 day 1, rituximab 375 mg/m2 day 1.

Abbreviations: ALL, acute lymphocytic leukaemia; BEAM, BCNU (carmustine) + etoposide + cytarabine + melphalan; B-NHL, B-cell non-Hodgkin lymphoma; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukaemia; CR, complete response; CVAD, cyclophosphamide + vincristine + doxorubicin + dexamethasone; CY, cyclophosphamide; EPOCH, etoposide + vincristine + doxorubicin + cyclophosphamide + prednisone; FLU, fludarabine; Fred Hutchinson, Fred Hutchinson Cancer Research Center; i.v., intravenous; MSKCC, Memorial Sloan Kettering Cancer Center; NCI, National Cancer Institute; NA, not applicable; ORR, overall response rate; OS, overall survival; PR, partial response; RFS, relapse-free survival; SD, stable disease; UPenn, University of Pennsylvania; VP etoposide.

Bispecific antibodies and derivatives

Wat zijn bispecifieke anti bodies?

Bispecifieke antilichamen en aanverwante derivaten zijn ontwikkeld door modulering van bepaalde eiwitten (proteïne-engineering) die de basis vormen van antilichamen om de valentie (mogelijkheid om vedrbindingen aan te gaan) te verhogen, wat de betrokkenheid van het immuunsysteem vergemakkelijkt. De initiële ontwikkeling van bispecifieke antilichamensamenstellingen had te maken met veel problemen die onderzoekers moesten zien te voorkomen, waaronder immunogeniciteit van het product, onvoldoende klinische activiteit en problemen bij grootschalige productie. Nieuwe platforms worden nu ontwikkeld voor de behandeling van vormen van lymfklierkanker en leukemie. (lees verder in studierapport)

(Bispecific antibodies and subsequent derivatives have been developed through protein engineering of the antibody backbone to increase valency, which facilitates engagement of the immune system. The initial development of bispecific-antibody constructs faced many challenges, including immunogenicity of the product, insufficient clinical activity, and difficulties in large-scale production. Novel platforms are being developed for the treatment of lymphoid malignancies.)

immuuntherapie bij vormen van lymfklierkanker en leukemie schema

Studies met

Immune-checkpoint inhibitors

Hier een schema van studies met anti-PD medicijnen. Nummer erachter correspondeert met literatuurlijst onderaan dit artikel:

Table 3

Clinical efficacy of immune-checkpoint inhibitors

Drug (manufacturer) and diseaseNumber of patientsTreatment scheduleResponse rate
Median duration of response (range)Survival outcomes
ORR (%)CR (%)PR (%)SD (%)
Nivolumab (BMS, USA)

B-NHL145* 31 1 mg/kg or 3 mg/kg week 1, week 4, and every 2 weeks thereafter 26 10 16 52 NA NA

DLBCL145* 11 1 mg/kg or 3 mg/kg week 1, week 4, and every 2 weeks thereafter 36 18 18 27 22 weeks (6–77 weeks) NA

Follicular lymphoma145* 10 1 mg/kg or 3 mg/kg week 1, week 4, and every 2 weeks thereafter 40 10 30 60 Not reached (27–82 weeks) NA

T-NHL145 23 3 mg/kg week 1, week 4, and every 2 weeks thereafter 17 0 17 43 NA NA

Hodgkin lymphoma145,148 23§ 1 mg/kg or 3 mg/kg week 1 and 4, and every 2 weeks thereafter 87 26 61 13 NA PFS: 86% at 24 weeks
OS: median not reached

Pembrolizumab (Merck, USA)

Hodgkin lymphoma150 29 10 mg/kg every 2 weeks 66 21 45 21 Not reached (1–185 days) NA

Ipilimumab (BMS, USA)

B-NHL154 18 3 mg/kg → 1 mg/kg × 3 doses (or 3 mg/kg × 4 doses in 6 patients) 11.1 5.6 5.6 NA NA NA

Hodgkin lymphoma (post alio SCT)172 14§ 0.1–3.0 mg/kg 14.3 14.3 0 14.3 NA NA
*Comprises DLBCL, follicular lymphoma, primary mediastinal B-cell lymphoma, and other B-cell lymphomas; data from this study for patients with DLBCL and follicular lymphoma are shown separately in the following two rows.
In reported abstract.
§In published report. Abbreviations: BMS, Bristol-Myers Squibb; B-NHL, B-cell non-Hodgkin lymphoma; CR, complete response; DLBCL, diffuse large-B-cell lymphoma; NR, not applicable or available; ORR, overall response rate; PR, partial response; SD, stable disease; T-NHL, T-cell non-Hodgkin lymphoma.
Conclusie:

We staan aan het begin van een interessant tijdperk van immunotherapeutische behandelingen voor lymfoïde maligniteiten. Veelbelovende resultaten met CAR T-cellen, bispecifieke antilichamen en hun derivaten en anti-PD medicijnen (checkpoint remmers) zijn inmiddels aangetoond, en zonder twijfel zullen vormen van immuuntherapie een van de centrale componenten worden van behandelingsopties bij lymfoïde maligniteiten, vooral bij recideiven of progrssie van de ziekte.

Ondanks het enthousiasme moeten wel nog enkele problemen worden overwonnen, waaronder technische modulering, met name van CAR-T-celtherapieën en bispecifieke antilichamen. Vergeleken met het verbluffende resultaat van zowel CAR-T-celtherapie als bispecifieke antilichamen bij de behandeling van ALL, zijn de resultaten die worden gezien bij patiënten met non-Hodgkin - NHL en Chronische Lymfatische Leukemie - CLL iets minder opvallend maar blijven veelbelovend; deze inconsistentie kan gedeeltelijk te wijten zijn aan de immuunonderdrukkende micro-omgeving geassocieerd met deze tumoren, hoewel verder onderzoek nodig is om dit verschil in werkzaamheid te verklaren.

Naast een verdere verkenning van de werkzaamheid, moeten we in detail het mechanisme van de acties van elke behandelingsmethode begrijpen om elke behandelingsoptie voor individuele patiënten beter te beheren en te volgen. Tot dusverre zijn er geen onderlinge vergelijkingsstudies uitgevoerd, hetgeen vergelijkingen tussen behandelingsmodaliteiten uitsluit. Elk platform heeft zijn eigen sterke en zwakke punten. Het vergelijkbare werkingsmechanisme van blinatumomab en op CD19 gerichte CAR T-cellen vertonen bijvoorbeeld een vergelijkbaar bijwerkingenprofiel. CIV-toediening van blinatumomab is ongemakkelijk, hoewel de korte halfwaardetijd van dit middel voordelig is omdat het een snelle toediening / werking van het geneesmiddel mogelijk maakt om de toxiciteit te minimaliseren.

De bij patiënten aanwezigheid en vermeerdering van CAR T-cellen resulteert in een variabele dosis-effect relatie tussen de verschillende patiënten; de levensduur van de T-cellen kan echter zorgen voor langdurige ziektebestrijding. Anti-PD-1-antilichamen hebben een opmerkelijke werkzaamheid tegen Hodgkin Lymfomen getoond, maar er zijn combinaties van behandelingen nodig om de CR - Complete Remissie percentages te verbeteren. De resultaten van lopende en toekomstige studies zullen ons in staat stellen om het verschil in gebruik van deze behandelingen te begrijpen als een enkele of een gecombineerde behandeling die de prognose van patiënten verbetert.

Het volledige studierapport: Novel immunotherapies in lymphoid malignancies isgratis in te zien. Hieronder het abstract met uitgebreide referentielijst.

We are entering an exciting era of immunotherapies for lymphoid malignancies. Promising results with CAR T cells, bispecific antibodies and their derivatives, and immune-checkpoint blockade have been demonstrated, and without doubt, immunotherapies will become one of the central components of treatment strategies in lymphoid malignancies, especially in the relapsed and/or refractory setting.

Nat Rev Clin Oncol. Author manuscript; available in PMC 2016 Jun 22.
Published in final edited form as:
PMCID: PMC4916838
NIHMSID: NIHMS782997

Novel immunotherapies in lymphoid malignancies

Abstract

The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens.

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In this Review, we describe the most promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.

Nat Rev Clin Oncol. Author manuscript; available in PMC 2017 Sep 25.
Published in final edited form as:
PMCID: PMC5611863
NIHMSID: NIHMS897656

The landscape of new drugs in lymphoma

Abstract

The landscape of drugs for the treatment of lymphoma has become crowded in light of the plethora of new agents, necessitating the efficient prioritization of drugs for expedited development. The number of drugs available, and the fact that many can be given for an extended period of time, has resulted in the emergence of new challenges; these include determining the optimal duration of therapy, and the need to balance costs, benefits, and the risk of late-onset toxicities. Moreover, with the increase in the number of available investigational drugs, the number of possible combinations is becoming overwhelming, which necessitates prioritization plans for the selective development of novel combination regimens. In this Review, we describe the mospromising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies that might enable more streamlined drug development. We also address new approaches for patient selection and for incorporating new end points into clinical trials.

Hundreds of new agents are currently being evaluated in preclinical and clinical settings for the treatment of cancer, and the failure rate of drug development processes remains very high1. The majority of agents are not successful owing to unacceptable toxicities and/or a lack of antitumour efficacy. Biomarkers to enable selection of patients for a specific therapy and the development of mechanism-based combination regimens are among the strategies that are being deployed to improve the success of drug development. However, drug development, unfortunately, remains a lengthy process that delays the availability of potentially life-saving new drugs. To help overcome these obstacles, innovative clinical trial designs that incorporate robust clinical end points and informative biomarkers are needed.

In recent years, several drugs have received regulatory approval for the treatment of lymphoma, including the antibody-drug conjugate brentuximab vedotin, the novel glycol-engineered anti-CD20 antibody obinutuzumab, the B-cell receptor signalling inhibitor ibrutinib, the PI3K-δ inhibitor idelalisib, and the immunomodulatory drug lenalidomide. Many unapproved targeted drugs have also demonstrated promising efficacy, including the BCL2 inhibitor venetoclax, the second-generation inhibitor of Bruton tyrosine kinase (BTK) acalabrutinib and several antibody-drug conjugates. In addition, various immunotherapies have also demonstrated efficacy in patients with lymphoma, such as mono-specific and bi-specific antibodies, immune-checkpoint inhibitors, and engineered chimeric antigen receptor (CAR) T cells. Thus, the drug landscape for lymphoma has become crowded, necessitating the rational prioritization of the development and selection of combination therapies for these patients. Herein, we provide an overview of the current landscape of drug development in lymphoma, including the mospromising agents currently in clinical testing, and provide expert opinion on new strategies that might enable streamlining of the drug development process.


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